Gyrase inhibitors and uses thereof

ABSTRACT

The present invention relates to compounds which inhibit bacterial gyrase and/or Topo IV and pharmaceutically acceptable compositions comprising said compounds. These compounds, and compositions thereof, are useful in treating bacterial infection. Accordingly, the present invention also relates to methods for treating bacterial infections in mammals.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application60/443,917 filed Jan. 31, 2003, the contents of which are incorporatedherein by reference.

FIELD OF THE INVENTION

This invention is in the field of medicinal chemistry and relates tocompounds, and pharmaceutical compositions thereof, that inhibitbacterial gyrase and Topo IV. The compounds are useful as inhibitors ofbacterial gyrase and Topo IV activity. The present invention alsorelates to methods for treating bacterial infections in mammals and tomethods for decreasing bacterial quantity in a biological sample.

BACKGROUND OF THE INVENTION

Bacterial resistance to antibiotics has long been recognized, and it istoday considered to be a serious worldwide health problem. As a resultof resistance, some bacterial infections are either difficult to treatwith antibiotics or even untreatable. This problem has become especiallyserious with the recent development of multiple drug resistance incertain strains of bacteria, such as Streptococcus pneumoniae (SP),Mycobacterium tuberculosis, and Enterococcus. The appearance ofvancomycin resistant enterococcus was particularly alarming becausevancomycin was formerly the only effective antibiotic for treating thisinfection, and had been considered for many infections to be the drug of“last resort”. While many other drug-resistant bacteria do not causelife-threatening disease, such as enterococci, there is the fear thatthe genes which induce resistance might spread to more deadly organismssuch as Staphylococcus aureus, where methicillin resistance is alreadyprevalent (De Clerq, et al., Current Opinion in Anti-infectiveInvestigational Drugs, 1999, 1, 1; Levy, “The Challenge of AntibioticResistance”, Scientific American, March, 1998).

Another concern is how quickly antibiotic resistance can spread. Forexample, until the 1960's SP was universally sensitive to penicillin,and in 1987 only 0.02% of the SP strains in the U.S. were resistant.However, by 1995 it was reported that SP resistance to penicillin wasabout seven percent and as high as 30% in some parts of the U.S. (Lewis,FDA Consumer magazine (September, 1995); Gershman in The MedicalReporter, 1997).

Hospitals, in particular, serve as centers for the formation andtransmission of drug-resistant organisms. Infections occurring inhospitals, known as nosocomial infections, are becoming an increasinglyserious problem. Of the two million Americans infected in hospitals eachyear, more than half of these infections resist at least one antibiotic.The Center for Disease Control reported that in 1992, over 13,000hospital patients died of bacterial infections that were resistant toantibiotic treatment (Lewis, “The Rise of Antibiotic-ResistantInfections”, FDA Consumer magazine, September, 1995).

As a result of the need to combat drug-resistant bacteria and theincreasing failure of the available drugs, there has been a resurgentinterest in discovering new antibiotics. One attractive strategy fordeveloping new antibiotics is to inhibit DNA gyrase, a bacterial enzymenecessary for DNA replication, and therefore, necessary for bacterialcell growth and division. Gyrase activity is also associated with eventsin DNA transcription, repair and recombination.

Gyrase is one of the topoisomerases, a group of enzymes which catalyzethe interconversion of topological isomers of DNA (see generally,Kornberg and Baker, DNA Replication, 2d Ed., Chapter 12, 1992, W.H.Freeman and Co.; Drlica, Molecular Microbiology, 1992, 6, 425; Drlicaand Zhao, Microbiology and Molecular Biology Reviews, 1997, 61, 377).Gyrase itself controls DNA supercoiling and relieves topological stressthat occurs when the DNA strands of a parental duplex are untwistedduring the replication process. Gyrase also catalyzes the conversion ofrelaxed, closed circular duplex DNA to a negatively superhelical formwhich is more favorable for recombination. The mechanism of thesupercoiling reaction involves the wrapping of gyrase around a region ofthe DNA, double strand breaking in that region, passing a second regionof the DNA through the break, and rejoining the broken strands. Such acleavage mechanism is characteristic of a type II topoisomerase. Thesupercoiling reaction is driven by the binding of ATP to gyrase. The ATPis then hydrolyzed during the reaction. This ATP binding and subsequenthydrolysis cause conformational changes in the DNA-bound gyrase that arenecessary for its activity. It has also been found that the level of DNAsupercoiling (or relaxation) is dependent on the ATP/ADP ratio. In theabsence of ATP, gyrase is only capable of relaxing supercoiled DNA.

Bacterial DNA gyrase is a 400 kilodalton protein tetramer consisting oftwo A (GyrA) and two B subunits (GyrB). Binding and cleavage of the DNAis associated with GyrA, whereas ATP is bound and hydrolyzed by the GyrBprotein. GyrB consists of an amino-terminal domain which has the ATPaseactivity, and a carboxy-terminal domain which interacts with GyrA andDNA. By contrast, eukaryotic type II topoisomerases are homodimers thatcan relax negative and positive supercoils, but cannot introducenegative supercoils. Ideally, an antibiotic based on the inhibition ofbacterial DNA gyrase would be selective for this enzyme and berelatively inactive against the eukaryotic type II topoisomerases.

The widely used quinolone antibiotics inhibit bacterial DNA gyrase.Examples of the quinolones include the early compounds such as nalidixicacid and oxolinic acid, as well as the later, more potentfluoroquinolones such as norfloxacin, ciprofloxacin, and trovafloxacin.These compounds bind to GyrA and stabilize the cleaved complex, thusinhibiting overall gyrase function, leading to cell death. However, drugresistance has also been recognized as a problem for this class ofcompounds (WHO Report, “Use of Quinolones in Food Animals and PotentialImpact on Human Health”, 1998). With the quinolones, as with otherclasses of antibiotics, bacteria exposed to earlier compounds oftenquickly develop cross-resistance to more potent compounds in the sameclass.

There are fewer known inhibitors that bind to GyrB. Examples include thecoumarins, novobiocin and coumermycin A1, cyclothialidine, cinodine, andclerocidin. The coumarins have been shown to bind to GyrB very tightly.For example, novobiocin makes a network of hydrogen bonds with theprotein and several hydrophobic contacts. While novobiocin and ATP doappear to bind within the ATP binding site, there is minimal overlap inthe bound orientation of the two compounds. The overlapping portions arethe sugar unit of novobiocin and the ATP adenine (Maxwell, Trends inMicrobiology, 1997, 5, 102).

For coumarin-resistant bacteria, the most prevalent point mutation is ata surface arginine residue that binds to the carbonyl of the coumarinring (Arg136 in E. coli GyrB). While enzymes with this mutation showlower supercoiling and ATPase activity, they are also less sensitive toinhibition by coumarin drugs (Maxwell, Mol. Microbiol., 1993, 9, 681).

Despite being potent inhibitors of gyrase supercoiling, the coumarinshave not been widely used as antibiotics. They are generally notsuitable due to their low permeability in bacteria, eukaryotic toxicity,and poor water solubility (Maxwell, Trends in Microbiology, 1997, 5,102). It would be desirable to have a new, effective GyrB inhibitor thatovercomes these drawbacks. Such an inhibitor would be an attractiveantibiotic candidate, without a history of resistance problems thatplague other classes of antibiotics.

Replication fork movement along circular DNA can generate topologicalchanges both ahead of the replication complex as well as behind in thealready replicated regions (Champoux, J. J., Annu. Rev. Biochem., 2001,70, 369-413). While DNA gyrase can introduce negative supercoils tocompensate for the topological stresses ahead of the replication fork,some overwinding can diffuse back into the already replicated region ofDNA resulting in precatenanes. If not removed, the presence of theprecatenanes can result in interlinked (catenated) daughter molecules atthe end of replication. TopoIV is responsible for separating thecatenated daughter plasmids as well as removal of precatenanes formedduring replication ultimately allowing for segragation of the daughtermolecules into daughter cells. Topo IV is composed of two ParC and 2pare subunits as a C2E2 tetramer (where the C and E monomers arehomologuous to the A and B monomers of gyrase, respectively) thatrequires ATP hydrolysis (at the N-terminus of the E subunit) to resetthe enzyme to re-enter the catalytic cycle. Topo IV is highly conservedamong bacteria and is essential for bacterial replication (Drlica andZhao, Microbiol. Mol. Biol. Rev., 1997, 61, 377).

While little attention has been paid to inhibitors that target ParE ofTopoIV, the action of the newer quinolones on the ParC region has beenwidely studied (Hooper, D. C., Clin. Infect. Dis., 2000, 31(Suppl 2):S24-28). It has been demonstrated that moxifloxacin and gatifloxacinhave more balanced activities against Gyrase and TopoIV resulting inexpanded Gram positive coverage as well as lower levels of resistancecaused primary-target mutation. In those cases, susceptibility islimited by the sensitivity of the second target to the antibacterialagent. Thus, agents that can effectively inhibit multiple essentialtargets can result in an expanded spectrum of potencies, improvedantibacterial potencies, improved potency against single target mutants,and/or lower spontaneous rates of resistance.

As bacterial resistance to antibiotics has become an important publichealth problem, there is a continuing need to develop newer and morepotent antibiotics. More particularly, there is a need for antibioticsthat represent a new class of compounds not previously used to treatbacterial infection. Such compounds would be particularly useful intreating nosocomial infections in hospitals where the formation andtransmission of resistant bacteria are becoming increasingly prevalent.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of gyrase and/or Topo IV. These compounds have the generalformula I:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², W, X, Z,and Ring A are as defined below.

These compounds, and pharmaceutically acceptable compositions thereof,are useful for treating or lessening the severity of bacterialinfections. In particular, the compounds of the present invention areuseful in treating or lessening the severity of urinary tractinfections, pneumonia, prostatitis, skin and soft tissue infections,intra-abdominal infections, blood stream infections, or infections offebrile neutropenic patients

DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   W is selected from nitrogen, CH, or CF;-   X is selected from CH or CF;-   Z is O or NH;-   R¹ is phenyl or a 5-6 membered heteroaryl ring having 1-3    heteroatoms independently selected from oxygen, nitrogen, or sulfur,    wherein:    -   R¹ is substituted with 0-3 groups independently selected from        -(T)_(y)-Ar, R′, oxo, C(O)R′, CO₂R′, OR′, N(R′)₂, SR′, NO₂,        halogen, CN, C(O)N(R′)₂, NR′C(O)R′, SO₂R′, SO₂N(R′)₂, or        NR′SO₂R′;-   y is 0 or 1;-   T is a straight or branched C₁₋₄ alkylidene chain, wherein one    methylene unit of T is optionally replaced by —O—, —NH—, or —S—;-   each R′ is independently selected from hydrogen, C₁₋₄ aliphatic, or    a 5-6 membered saturated, unsaturated, or aryl ring having 0-3    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    wherein:    -   R′ is substituted with 0-3 groups independently selected from        halogen, oxo, R^(o), N(R^(o))₂, OR^(o), CO₂R^(o),        NR^(o)C(O)R^(o), C(O)N(R^(o))₂, SO₂R^(o), SO₂N(R^(o))₂, or        NR^(o)SO₂R^(o), wherein:    -   each R^(o) is independently selected from hydrogen, C₁₋₄        aliphatic, or a 5-6 membered saturated, unsaturated, or aryl        ring having 0-3 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, and wherein:    -   two substituents on adjacent positions of R¹ may be taken        together to form a 5-7 membered saturated, partially        unsaturated, or aryl ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;-   Ar is a 3-8 membered saturated, unsaturated, or aryl ring, a 3-7    membered heterocyclic ring having 1-3 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 5-6 membered    heteroaryl ring having 1-3 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, wherein:    -   Ar is substituted with 0-3 groups independently selected from        R′, oxo, CO₂R′, OR′, N(R′)₂, SR′, NO₂, halogen, CN, C(O)N(R′)₂,        NR′C(O)R′, SO₂R′, C(O)R′, SO₂N(R′)₂, or NR′SO₂R′;-   R² is selected from hydrogen or a C₁₋₃ aliphatic group; and    -   Ring A is a 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur,        provided that said ring has a hydrogen-bond acceptor in the        position adjacent to the point of attachment to Ring B, wherein:    -   Ring A is substituted with 0-3 groups independently selected        from R′, oxo, CO₂R′, OR′, N(R′)₂, SR′, NO₂, halogen, CN,        C(O)N(R′)₂, NR′C(O)R′, SO₂R′, SO₂N(R′)₂, or NR′SO₂R′, and        wherein:    -   two substituents on adjacent positions of Ring A may be taken        together to form a 5-7 membered saturated, partially        unsaturated, or aryl ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur.

As used herein, the following definitions shall apply unless otherwiseindicated.

The phrase “optionally substituted” is used interchangeably with thephrase “substituted or unsubstituted.” Unless otherwise indicated, anoptionally substituted group may have a substituent at eachsubstitutable position of the group, and each substitution isindependent of the other.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain or branched C₁-C₈ hydrocarbon chain that is completelysaturated or that contains one or more units of unsaturation, or amonocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic (also referred to herein as “carbocycle” or“cycloalkyl”), that has a single point of attachment to the rest of themolecule wherein any individual ring in said bicyclic ring system has3-7 members. For example, suitable aliphatic groups include, but are notlimited to, linear or branched or alkyl, alkenyl, alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and“alkoxycarbonyl”, used alone or as part of a larger moiety include bothstraight and branched chains containing one to twelve carbon atoms. Theterms “alkenyl” and “alkynyl” used alone or as part of a larger moietyshall include both straight and branched chains containing two to twelvecarbon atoms.

The term “heteroatom” means nitrogen, oxygen, or sulfur and includes anyoxidized form of nitrogen and sulfur, and the quaternized form of anybasic nitrogen. Also the term “nitrogen” includes a substitutablenitrogen of a heterocyclic ring. As an example, in a saturated orpartially unsaturated ring having 0-3 heteroatoms selected from oxygen,sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation, and includes aryl rings.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic and whereineach ring in the system contains 3 to 7 ring members. The term “aryl”may be used interchangeably with the term “aryl ring”. The term “aryl”also refers to heteroaryl ring systems as defined hereinbelow.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinmeans non-aromatic, monocyclic, bicyclic or tricyclic ring systemshaving five to fourteen ring members in which one or more ring membersis a heteroatom, wherein each ring in the system contains 3 to 7 ringmembers.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

The term “hydrogen bond acceptor”, as used herein, means an atom capableof accepting a hydrogen bond. A typical hydrogen bond acceptor is asulfur, oxygen, or nitrogen atom, especially a nitrogen that issp²-hybridized, an ether oxygen, or a thioether sulfur. A preferredhydrogen bond acceptor is a nitrogen that is sp²-hybridized.

A combination of substituents or variables is permissible only if such acombination results in a stable or chemically feasible compound. Astable compound or chemically feasible compound is one that is notsubstantially altered when kept at a temperature of 40° C. or less, inthe absence of moisture or other chemically reactive conditions, for atleast a week.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C— or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools or probes in biological assays.

Examples of suitable Ring A moieties are set forth in Table 1 below.

TABLE 1 a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

bb

cc

dd

ee

ff

gg

hh

wherein each Ring A is optionally substituted as defined above.

According to one embodiment, Ring A of formula I is a 5-memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, provided that said ring has a hydrogen-bondacceptor in the position adjacent to the point of attachment to Ring B,wherein said Ring A is optionally substituted as defined herein supra.

According to another embodiment, Ring A of formula I is a 6-memberedheteroaryl ring having 1-3 nitrogens, provided that said ring has anitrogen atom in the position adjacent to the point of attachment toRing B, wherein said Ring A is optionally substituted as defined hereinsupra.

In certain embodiments, Ring A moieties of formula I are selected fromrings a, b, c, d, e, f, g, h, i, j, k, l, m, p, q, r, s, t, v, w, x, y,z, aa, bb, cc, dd, and ee, wherein each Ring A is optionally substitutedas defined above.

In other embodiments, the Ring A moieties of formula I are selected fromrings a, f, l, s, w, y, and z, wherein each Ring A is optionallysubstituted as defined above.

When Ring A of formula I is a bicyclic heteroaryl ring, preferredbicyclic Ring A moieties include benzothiazole, benzimidazole,benzoxazole, and quinoline.

According to one embodiment, substituents on Ring A of formula I, ifpresent, are selected from oxo, N(R′)₂, C(O)N(R′)₂, CO₂R′, halogen,N(R′)SO₂R′, C(O)R′, OR′, or R′. According to another embodiment, R′substituents on Ring A of formula I include methyl, ethyl, propyl,piperazinyl, piperidinyl, or morpholinyl, wherein said R′ groups areoptionally substituted with R^(o), N(R^(o))₂ or OR^(o).

According to one embodiment, the R¹ group of formula I is optionallysubstituted phenyl.

According to another embodiment, the R¹ group of formula I is anoptionally substituted 5-membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

According to another embodiment, the R¹ group of formula I is anoptionally substituted 5-membered heteroaryl ring having 1-3 nitrogens.

Yet another embodiment of the present invention relates to a compound offormula I wherein R¹ is an optionally substituted 6-membered heteroarylring having 1-2 nitrogens.

In certain embodiments, the R¹ group of formula I is selected from anoptionally substituted phenyl or 5-6 membered heteroaryl ring having 1-2nitrogens. In other embodiments, the R¹ group of formula I is selectedfrom an optionally substituted pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,pyridone, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,pyrimidin-6-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, orimidazol-5-yl ring. According to yet another embodiment, the R¹ group offormula I is an optionally substituted ring selected from pyrid-3-yl,pyrid-4-yl, pyridone, pyrimidin-5-yl, or imidazol-1-yl.

In certain embodiments, substituents on the R¹ group of formula I, whenpresent, are selected from halogen, oxo, -(T)_(y)-Ar, R′, CO₂R′, OR′,N(R′)₂, SR′, C(O)N(R′)₂, NR′C(O)R′, SO₂R′, SO₂N(R′)₂, or NR′SO₂R′.According to other embodiments, substituents on the R¹ group of formulaI, when present, are selected from oxo, fluoro, chloro, N(CH₃)₂,NHCH₂CH₃, NH-cyclopropyl, NH₂, NHC(O)CH₃, C(O)NHcyclopropyl, methyl,ethyl, t-butyl, isobutyl, cyclopropyl, isopropyl, CH₂phenyl,CH₂pyridin-3-yl, OH, OCH₃, OCH₂CH₃, OCH₂phenyl, OCH₂pyridin-3-yl,CH₂piperidinyl, CH₂cyclopropyl, or CH₂CH₂OCH₃.

According to one embodiment, R¹ is substituted with -(T)_(y)-Ar whereinT is a straight or branched C₁₋₃ alkylidene chain wherein one methyleneunit of T is optionally replaced by —O—, —NH—, or —S—. According toanother embodiment, T is a straight or branched C₁₋₃ alkylidene chainwherein one methylene unit of T is replaced by —O—, —NH—, or —S—. Yetanother embodiment of the present invention relates to a compound offormula I wherein R¹ is substituted with -(T)_(y)-Ar and Ar is anoptionally substituted 5-6 membered saturated ring having 1-2heteroatoms independently selected from oxygen, nitrogen, or sulfur.According to another embodiment, the Ar group of formula I is anoptionally substituted 5-membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. According toyet another embodiment, the Ar group of formula I is an optionallysubstituted 6-membered heteroaryl ring having 1-3 nitrogens. Yet anotherembodiment relates to a compound of formula I wherein Ar is optionallysubstituted phenyl.

When the R¹ group of formula I is substituted with -(T)_(y)-Ar, examplesof substituents on Ar include halogen, OR′, R′, CO₂R′, SO₂R′, oxo, andC(O)R′.

According to one embodiment, when two substituents on adjacent positionsof R¹ of formula I are taken together to form an optionally substitutedring fused to R¹, rings formed thereby include 5-6 membered saturated,partially unsaturated, or aryl rings having 0-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. According toanother embodiment, said ring fused to R¹ is selected from a 5-memberedsaturated ring having two oxygens or a 6-membered saturated ring havingtwo oxygens. Examples of substituents on said ring fused to R¹ includehalogen, such as fluorine.

One embodiment of the present invention relates to a compound of formulaI wherein R² is selected from methyl, ethyl, isopropyl, or cyclopropyl.According to another embodiment, R² is methyl or ethyl. According to yetanother embodiment, R² of formula I is ethyl.

According to one embodiment, the present invention relates to a compoundof formula I wherein Z is NH.

According to another embodiment, the present invention relates to acompound of formula I wherein Z is O.

Compounds of the present invention fall within the genus of compoundsdescribed in PCT/US 01/48855. However, applicants have discovered thatthe presence of the Ring A moiety, as defined above, imparts surprisingand unexpectedly increased gyrase inhibitory, TopoIV activity, andantimicrobial potency.

According to one embodiment, the present invention relates to a compoundof formula II:

or a pharmaceutically acceptable salt thereof, wherein Z, R² and Ring Aare as defined above and the imidazole ring depicted is optionallysubstituted in the 4-position with C(O)N(R′)₂ and/or substituted in the2-position with R′. Accordingly, another embodiment of the presentinvention relates to a compound of formula II-a:

or a pharmaceutically acceptable salt thereof, wherein Z, R², R′, andRing A are as defined above.

Other embodiments describing R² and Ring A groups of formula II-a arethose described for formula I above.

Other embodiments describing R′ groups of formula II-a are selected fromhydrogen or C₁₋₄ aliphatic.

According to one embodiment, the present invention relates to a compoundof formula II or II-a wherein Z is NH.

According to another embodiment, the present invention relates to acompound of formula II or II-a wherein Z is O.

According to another embodiment, the present invention relates to acompound of formula III:

or a pharmaceutically acceptable salt thereof, wherein Z, R² and Ring Aare as defined above, and the pyridone ring depicted is substituted with0-2 groups independently selected from —(CH₂)_(y)—Ar, halogen, oxo, R′,CO₂R′, OR′, N(R′)₂, SR′, C(O)N(R′)₂, NR′C(O)R′, SO₂R′, SO₂N(R′)₂, orNR′SO₂R′.

Other embodiments describing R² and Ring A groups of formula III arethose described for formula I above.

Other embodiments describing substituents on the pyridone ring offormula III are those described above as preferred substituents on R¹ offormula I.

According to one embodiment, the present invention relates to a compoundof formula III wherein Z is NH.

According to another embodiment, the present invention relates to acompound of formula III wherein Z is O.

According to another embodiment, the present invention relates to acompound of formula III-a:

or a pharmaceutically acceptable salt thereof, wherein Z, R′, R² andRing A are as defined above.

Other embodiments describing R² groups of formula III-a are thosedescribed for R² groups of formula I above.

Other embodiments describing Ring A groups of formula III-a are thosedescribed for Ring A groups of formula I above.

In certain embodiments, the R′ substituents on the pyridone ring offormula III-a are selected from hydrogen or C₁₋₄ aliphatic wherein R′ isoptionally substituted with phenyl or pyridyl. In other embodiments, theR′ substituents on the pyridone ring of formula III-a are selected frommethyl, ethyl, t-butyl, isobutyl, cyclopropyl, isopropyl, CH₂phenyl,CH₂pyridin-3-yl, CH₂piperidinyl, CH₂cyclopropyl, or CH₂CH₂OCH₃.

According to one embodiment, the present invention relates to a compoundof formula III-a wherein Z is NH.

According to another embodiment, the present invention relates to acompound of formula III-a wherein Z is O.

Yet another embodiment of the present invention relates to a compound offormula IV:

or a pharmaceutically acceptable salt thereof, wherein y, Z, T, Ar, R²and Ring A are as defined above.

Other embodiments describing Ring A and R² groups of formula IV arethose set forth for those Ring A and R² groups of formula I, supra.

According to one embodiment, the Ar group of formula IV is an optionallysubstituted 5-6 membered saturated ring having 1-2 heteroatomsindependently selected from oxygen, nitrogen, or sulfur.

According to another embodiment, the Ar group of formula IV is anoptionally substituted 5-membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

According to another embodiment, the Ar group of formula IV is anoptionally substituted 6-membered heteroaryl ring having 1-3 nitrogens.

Yet another embodiment relates to a compound of formula IV wherein Ar isoptionally substituted phenyl.

According to one embodiment, the present invention relates to a compoundof formula IV wherein Z is NH.

Examples of substituents on the Ar group of formula IV include halogen,OR′, R′, CO₂R′, SO₂R′, oxo, and C(O)R′.

According to another embodiment, the present invention relates to acompound of formula IV wherein Z is O.

Yet another embodiment of the present invention relates to a compound offormula V:

or a pharmaceutically acceptable salt thereof, wherein y, Z, R² and R¹are as defined above.

Other embodiments describing R¹ and R² groups of formula V are those setforth for those R¹ and R² groups of formula I, supra.

According to one embodiment, the present invention relates to a compoundof formula V wherein Z is NH.

Examples of substituents on the Ar group of formula IV include halogen,OR′, R′, CO₂R′, SO₂R′, oxo, and C(O)R′.

According to another embodiment, the present invention relates to acompound of formula V wherein Z is O.

According to another embodiment of the present invention relates to acompound of formula VI:

or a pharmaceutically acceptable salt thereof, wherein y, Z, T, Ar, andR² are as defined above.

Other embodiments describing the R² group of formula VI are those setforth for the R² group of formula I, supra.

According to one embodiment, the Ar group of formula VI is an optionallysubstituted 5-6 membered saturated ring having 1-2 heteroatomsindependently selected from oxygen, nitrogen, or sulfur.

According to another embodiment, the Ar group of formula VI is anoptionally substituted 5-membered heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

According to another embodiment, the Ar group of formula VI is anoptionally substituted 6-membered heteroaryl ring having 1-3 nitrogens.

Yet another embodiment relates to a compound of formula VI wherein Ar isoptionally substituted phenyl.

According to one embodiment, the present invention relates to a compoundof formula VI wherein Z is NH.

Examples of substituents on the Ar group of formula VI include halogen,OR′, R′, CO₂R′, SO₂R′, oxo, and C(O)R′.

According to another embodiment, the present invention relates to acompound of formula VI wherein Z is O.

Exemplary structures of formula I are set forth in Table 2 below.

TABLE 2 I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-28

I-29

I-30

I-31

I-32

I-35

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

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The compounds of this invention may be prepared in general by methodsknown to those skilled in the art for analogous compounds, asillustrated by the general Schemes I, II, III, and IV shown below andthe Examples set forth infra.

Scheme I above shows a general method for preparingN′-alkyl-N-cyanoureas (3) useful in the preparation of the compounds ofthe present invention wherein Z is NH. At step (a), cyanamide (2) istreated with an alkyl isocyanate in aqueous sodium hydroxide to afford,after acidification, compound 3. One of skill in the art would recognizethat a variety of alkyl isocyanates would be amenable to the reactionconditions of Scheme I to form a variety of N′-alkyl-N-cyanoureas.

Scheme II above shows a general method for preparing the benzimidazolecompounds of the present invention wherein Z is NH or O. Thebromo-aniline (4) is treated with sodium perborate and acetic acid toform the difluoro-nitro compound (5). Compound 5 is treated with Ring Ain the presence of sodium hydride to afford the biaryl compound 6. Theremaining fluoro group of compound 6 is displaced with ammonia to formthe amino compound (7). The 2-nitro-5-bromoaniline (7) is then coupledto an aryl boronic acid, at step (d), in the presence of palladium toform the tri-aryl compound (8). The nitro group of compound 8 is reducedto form a diamino compound which is treated with an N′-alkyl-N-cyanourea(3) to form benzimidazole compound of formula I wherein Z is NH (9).

Alternatively, intermediate 8 may be used to form compounds of formula Iwherein Z is O. Compound 10 is formed by treating 8, after reduction tothe diamino compound, with 2-methyl-2-thiopseudourea andR²-chloroformate according to the method described by L. I. Kruse et al,J. Med. Chem. 1989, 32, 409-417. One of ordinary skill in the art wouldrecognize that the reactions depicted in Scheme II above are amenable toa variety of R¹ and Ring A groups of the present invention.

In an alternative method, intermediate 8 is treated with eitherN,N-diethlycarboxy-2-methyl-2-thiopseudourea orN,N-diethlyureamido-2-methyl-2-thiopseudourea to form compounds 10 and9, respectively. The synthesese of bothN,N-diethlycarboxy-2-methyl-2-thiopseudourea andN,N-diethlyureamido-2-methyl-2-thiopseudourea are described in theExamples set forth infra.

Scheme III above shows a general method for preparing compounds offormula II-a using methods substantially similar to those described byKiyomori, A.; Marcoux, J.-F.; Buchwald, S. L., Tetrahedron Letters, vol.40, (1999) 2657-2660. Compound 7 is treated with diboranic ester in thepresence of Pd(dppf)/potassium acetate in DMSO at 80° C. to affordintermediate 11. Compound 11 is treated with 4-C(O)N(R′)₂-imidazole inthe presence of copper acetate to form the 4-C(O)N(R′)₂-imidazol-1-ylcompound 12. Compounds of formula II-a are prepared from compound 12 asdescribed in Scheme II, steps (e), (f), and (g).

Although 4-C(O)N(R′)₂-imidazole is used to exemplify, one of ordinaryskill in the art would recognize that a variety of R¹ groups areamenable to the displacement reaction at step (c) to form a variety ofcompounds of the present invention. Generally, the boronate intermediate11 may be treated with a variety of R¹-halides or R¹-triflates, usingmethods well known to one of ordinary skill in the art, to formintermediate compounds 12′ as shown below. Using the methods recitedherein and those known to one of ordinary skill in the art, compounds12′ are useful for preparing compounds 9 and 10 of the present inventionas depicted above at Scheme II.

Scheme IV above shows an alternate method for preparing compounds offormula II-a. Compound 13 is nitrated to form 14. Compound 14 is treatedwith ammonium hydroxide to form the amino compound 15. The bromo groupof compound 15 is treated with the BrZn-Ring A reagent in the presenceof Pd(PPh₃)₄ in THF to form compound 16. Compound 16 is treated with the4-C(O)N(R′)₂-imidazole in the presence of sodium carbonate to form the4-C(O)N(R′)₂-imidazol-1-yl compound 18. Compounds of formula II-a arethen prepared from compound 18 as described in Scheme II, steps (e),(f), and (g).

One of skill in the art would recognize that a variety of compounds ofthe present invention may be prepared according to the general method ofSchemes I, II, III, and IV, methods known in the art, and the syntheticExamples set forth below.

The compounds of this invention are potent inhibitors of gyrase and TopoIV as determined by enzymatic assay. These compounds have also beenshown to have antimicrobial activity in an antimicrobial susceptibilityassay. The activity of a compound utilized in this invention as aninhibitor of gyrase or Topo IV may be assayed in vitro, in vivo or in acell line according to methods known in the art. The details of theconditions used for both the enzymatic and the antimicrobialsusceptibility assays are set forth in the Examples below.

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier, adjuvant, orvehicle. The amount of compound in the compositions of this invention issuch that is effective to detectably inhibit gyrase, Topo IV, or tomeasurably decrease bacterial quantity, in a biological sample or in apatient. Preferably the composition of this invention is formulated foradministration to a patient in need of such composition. Mostpreferably, the composition of this invention is formulated for oraladministration to a patient.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of gyrase and/or Topo IV activity in a biological sample isuseful for a variety of purposes that are known to one of skill in theart. Examples of such purposes include, but are not limited to, bloodtransfusion, organ-transplantation, biological specimen storage, andbiological assays.

The term “patient”, as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

The term “detectably inhibit”, as used herein means a measurable changein gyrase, or Topo IV, activity between a sample comprising saidcomposition and gyrase, or Topo IV, and an equivalent sample comprisinggyrase, or Topo IV in the absence of said composition.

As used herein, the term “measurably decrease bacterial quantity”, asused herein means a measurable change in the number of bacteria betweena sample containing said composition and a sample containing onlybacteria.

A “pharmaceutically acceptable salt” means any non-toxic salt of acompound of this invention that, upon administration to a recipient, iscapable of providing, either directly or indirectly, a compound of thisinvention or an inhibitorily active metabolite or residue thereof. Asused herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof gyrase and/or Topo IV.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acid salts includeacetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodiumand potassium), alkaline earth metal (e.g., magnesium), ammonium andN⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternizationof any basic nitrogen-containing groups of the compounds disclosedherein. Water or oil-soluble or dispersible products may be obtained bysuch quaternization.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this invention may beorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, aqueous suspensions or solutions. Inthe case of tablets for oral use, carriers commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

The pharmaceutically acceptable compositions of this invention may alsobe administered topically, especially when the target of treatmentincludes areas or organs readily accessible by topical application,including diseases of the eye, the skin, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositionsmay be formulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutically acceptable compositions canbe formulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or, preferably, as solutions in isotonic, pH adjusted sterilesaline, either with or without a preservative such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticallyacceptable compositions may be formulated in an ointment such aspetrolatum.

The pharmaceutically acceptable compositions of this invention may alsobe administered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of thisinvention are formulated for oral administration.

Dosage levels of between about 0.01 and about 100 mg/kg body weight perday, preferably between 0.5 and about 75 mg/kg body weight per day andmost preferably between about 1 and 50 mg/kg body weight per day of theactive ingredient compound are useful in a monotherapy for theprevention and treatment of bacterial infections caused by bacteria suchas Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcusfaecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps.Proteus sps. Pseudomonas aeruginosa, E. coli, Serratia marcesens,Staphylococcus aureus, Coag. Neg. Staph, Haemophilus influenzae,Bacillus anthracis, Mycoplasma pneumoniae, Moraxella catarralis,Chlamydia pneumoniae, Legionella pneumophila, Mycobacteriumtuberculosis, Staphylococcus epidermidis, or Helicobacter pylori.

Typically, the pharmaceutical compositions of this invention will beadministered from about 1 to 5 times per day or alternatively, as acontinuous infusion. Or, alternatively, the compositions of the presentinvention may be administered in a pulsatile formulation. Suchadministration can be used as a chronic or acute therapy. The amount ofactive ingredient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Preferably,such preparations contain from about 20% to about 80% active compound.

When the compositions of this invention comprise a combination of acompound of formula I and one or more additional therapeutic orprophylactic agents, both the compound and the additional agent shouldbe present at dosage levels of between about 10% to 80% of the dosagenormally administered in a monotherapy regime.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence or disease symptoms.

As the skilled artisan will appreciate, lower or higher doses than thoserecited above may be required. Specific dosage and treatment regimensfor any particular patient will depend upon a variety of factors,including the activity of the specific compound employed, the age, bodyweight, general health status, sex, diet, time of administration, rateof excretion, drug combination, the severity and course of the disease,and the patient's disposition to the disease and the judgment of thetreating physician.

Depending upon the particular condition, or disease, to be treated orprevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may also be present inthe compositions of this invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease, or condition, are known as “appropriate for thedisease, or condition, being treated”. Such agents include, but are notlimited to, an antibiotic, an anti-inflammatory agent, a matrixmetalloprotease inhibitor, a lipoxygenase inhibitor, a cytokineantagonist, an immunosuppressant, an anti-cancer agent, an anti-viralagent, a cytokine, a growth factor, an immunomodulator, a prostaglandin,an anti-vascular hyperproliferation compound, or an agent whichincreases the susceptibility of bacterial organisms to antibiotics.

Agents which increase the susceptibility of bacterial organisms toantibiotics are known. For example, U.S. Pat. No. 5,523,288, U.S. Pat.No. 5,783,561 and U.S. Pat. No. 6,140,306 describe methods of usingbactericidal/permeability-increasing protein (BPI) for increasingantibiotic susceptibility of gram-positive and gram-negative bacteria.Agents that increase the permeability of the outer membrane of bacterialorganisms have been described by Vaara, M. in Microbiological Reviews(1992) pp. 395-411, and the sensitization of gram-negative bacteria hasbeen described by Tsubery, H., et al, in J. Med. Chem. (2000) pp.3085-3092.

According to another embodiment, the invention provides a method fortreating or lessening the severity of a bacterial infection in a patientcomprising the step of administering to said patient a compositionaccording to the present invention.

According to another embodiment, the invention provides a method ofinhibiting gyrase in a biological sample.

According to another embodiment, the invention provides a method ofinhibiting Topo IV in a biological sample.

According to another embodiment, the invention provides a method ofdecreasing bacterial quantity in a biological sample.

According to another embodiment, the invention provides a method ofdecreasing bacterial quantity in a biological sample, but furthercomprising the step of contacting said biological sample with an agentwhich increases the susceptibility of bacterial organisms toantibiotics.

The pharmaceutical compositions and methods of this invention will beuseful generally for controlling bacterial infections in vivo. Examplesof bacterial organisms that may be controlled by the compositions andmethods of this invention include, but are not limited to, the followingorganisms: Streptococcus pneumoniae, Streptococcus pyogenes,Enterococcus faecalis, Enterococcus faecium, Klebsiella pneumoniae,Enterobacter sps. Proteus sps. Pseudomonas aeruginosa, E. coli, Serratiamarcesens, Staphylococcus aureus, Coag. Neg. Staph, Haemophilusinfuenzae, Bacillus anthracis, Mycoplasma pneumoniae, Moraxellacatarralis, H. influenzae, Chlamydia pneumoniae, Legionella pneumophila,Mycobacterium tuberculosis, Helicobacter pylori, Staphylococcusepidermidis. Chlamydia pneumoniae, Legionella pneumophila, Mycobacteriumtuberculosis, or Helibacter pylori.

The compositions and methods will therefore be useful for controlling,treating or reducing the advancement, severity or effects of nosocomialor non-nosocomial infections. Examples of nosocomial uses include, butare not limited to, urinary tract infections, respiratory infectionssuch as pneumonia, surgical wound infections, and blood streaminfections (also known as bacteremia). Examples of non-nosocomial usesinclude but are not limited to urinary tract infections, pneumonia,prostatitis, skin and soft tissue infections, intra-abdominalinfections, and therapy for febrile neutropenic patients.

The term “pharmaceutically effective amount” refers to an amounteffective in treating or ameliorating a bacterial infection in apatient. The term “prophylactically effective amount” refers to anamount effective in preventing or substantially lessening a bacterialinfection in a patient.

The compounds of this invention may be employed in a conventional mannerfor controlling bacterial infections levels in vivo and for treatingdiseases or reducing the advancement or severity of effects which aremediated by bacteria. Such methods of treatment, their dosage levels andrequirements may be selected by those of ordinary skill in the art fromavailable methods and techniques.

For example, a compound of this invention may be combined with apharmaceutically acceptable adjuvant for administration to a patientsuffering from a bacterial infection or disease in a pharmaceuticallyacceptable manner and in an amount effective to lessen the severity ofthat infection or disease.

Alternatively, the compounds of this invention may be used incompositions and methods for treating or protecting individuals againstbacterial infections or diseases over extended periods of time. Thecompounds may be employed in such compositions either alone or togetherwith other compounds of this invention in a manner consistent with theconventional utilization of enzyme inhibitors in pharmaceuticalcompositions. For example, a compound of this invention may be combinedwith pharmaceutically acceptable adjuvants conventionally employed invaccines and administered in prophylactically effective amounts toprotect individuals over an extended period of time against bacterialinfections or diseases.

The compounds of formula I may also be co-administered with otherantibiotics to increase the effect of therapy or prophylaxis againstvarious bacterial infections. When the compounds of this invention areadministered in combination therapies with other agents, they may beadministered sequentially or concurrently to the patient. Alternatively,pharmaceutical or prophylactic compositions according to this inventioncomprise a combination of a compound of formula I and anothertherapeutic or prophylactic agent.

The additional therapeutic agents described above may be administeredseparately, as part of a multiple dosage regimen, from theinhibitor-containing composition. Alternatively, these agents may bepart of a single dosage form, mixed together with the inhibitor in asingle composition.

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

EXAMPLES Example 1

5-Bromo-1,3-difluoro-2-nitro-benzene: To a suspension of sodiumperborate tetrahydrate (1.04 g, 5 mmol) in acetic acid (20 mL), stirredat 55° C., was added a solution of 4-bromo-2,6-difluoroaniline in aceticacid (10 mL) over 1 hour in a dropwise fashion. After stirring at 55° C.for an additional 3 hours, the solution was allowed to cool to roomtemperature and filtered. The filtrate was poured into ice, andextracted twice with ethyl acetate. The combined organic extracts werewashed successively with 5×100-mL portions of water, brine, dried(MgSO₄), and concentrated in vacuo. The resulting residue was purifiedby column chromatography over silica gel eluted with ethylacetate:hexanes (1:20) to afford 780 mg of the title compound as a tansolid. ¹H NMR (CDCl₃) δ 7.32 (dt, 2H).

Example 2

1-(5-Bromo-3-fluoro-2-nitro-phenyl)-1H-pyrazole: To a suspension ofsodium hydride (44 mg, 1.1 mmol, 60% oil dispersion) in THF (4 mL),stirred at 0° C., was added a solution of pyrazole (72 mg, 1.05 mmol) inTHF (1 mL). The resulting mixture was stirred at 0° C. for 5 minutes anda solution of 5-bromo-1,3-difluoro-2-nitro-benzene (238 mg, 1 mmol) inTHF (1 mL) was added. The mixture was stirred at room temperature for 1hour, quenched by addition of water (1 mL), then partitioned betweenwater (20 mL) and ethyl acetate (50 mL). The organic layer was washedwith brine, dried (MgSO₄), and concentrated in vacuo. The residue waspurified by column chromatography over silica gel eluted with ethylacetate:hexanes (1:6), to afford 240 mg (86%) of the title compound. ¹HNMR (CDCl₃) δ 6.55 (t, 1H), 7.45 (d, 1H), 7.60 (s, 1H), 7.80 (m, 2H). MSM+1 287, M+1+2 289.

Example 3

5-Bromo-2-nitro-3-pyrazol-1-yl-phenylamine: To a solution of1-(5-bromo-3-fluoro-2-nitro-phenyl)-1H-pyrazole (240 mg, 0.84 mmol) inethanol (3 mL) was added ammonia (3 mL, 2N in methanol. The resultingmixture was heated in a sealed tube at 80° C. for 16 hours thenconcentrated in vacuo. The residue was purified by column chromatographyover silica gel eluted with ethyl acetate:hexanes (1:3) to afford 205 mg(86%) of the title compound as a yellow solid. ¹H NMR (CDCl₃) δ 5.20 (brs, 2H), 6.50 (t, 1H), 6.9 (d, 1H), 7.1 (d, 1H), 7.7 (d, 1H), 7.8 (d,1H). MS M+1 283, M+1+2 285.

Example 4

2-Nitro-3-pyrazol-1-yl-5-pyridin-3-yl-phenylamine: To a solution of5-bromo-2-nitro-3-pyrazol-1-yl-phenylamine (200 mg, 0.71 mmol) in THF (8mL) was added, successively, 3-pyridyl-diethyl borane (157 mg),(tetrakistriphenylphosphine) palladium(0) (84 mg), and sodium carbonate(1.1 mL, 2.2 mmom of 2M aqueous). The resulting mixture was stirred at70° C. overnight then cooled to room temperature. The reaction mixturewas diluted with ethyl acetate (100 mL) and washed with water (50 mL),brine (50 mL), dried (MgSO₄) then concentrated in vacuo. The resultingresidue was purified by column chromatography over silica gel elutedwith a gradient of ethyl acetate:hexanes (1:3, 1:2, 1:0, 2:1, 4:1, 8:1),to afford 120 mg (60%) of the title compound as a yellow solid. ¹H NMR(DMSO-d₆) δ 6.45 (br, s 2H), 6.55 (t, 1H), 7.1 (s, 1H), 7.25 (s, 1H),7.55 (m, 1H), 7.7 (s, 1H), 8.1 (dt, 1H), 8.3 (d, 1H), 8.7 (d, 1H), 8.9(s, 1H).

Example 5

1-Ethyl-3-(7-pyrazol-1-yl-5-pyridin-3-yl-1H-benzoimidazol-2-yl)-urea(1-2): A suspension of 2-nitro-3-pyrazol-1-yl-5-pyridin-3-yl-phenylamine(120 mg, 0.40 mmol) and 10% palladium on carbon (12 mg) in ethyl acetate(10 mL) was placed in a Parr hydrogenator under a hydrogen pressure of45 psi. The mixture was shaken for 16 hours, filtered and the filtrateconcentrated in vacuo. The resulting residue was diluted with H₂SO₄ (1.6mL or IN), and N′-ethyl-N-cyanourea (0.8 mL, 1M) was added. The mixturewas heated at 95° C. for 4 hours then concentrated in vacuo. The residuewas purified by preparative HPLC to afford 75 mg of the title compoundas the bis-TFA salt which was converted to the free base to afford thetitle compound. ¹H NMR (DMSO-d₆) δ 1.1 (t, 3H), 3.2 (m, 2H), 7.0 (m,1H), 7.3 (d, 1H), 7.5 (m, 1H), 7.55 (s, 1H), 8.0 (d, 1H), 8.55 (dd, 1H),8.85 (s, 1H), 10.1 (s, 1H), 12.0 (s, 1H). LC/MS one peak, M+1 348.23,M−1 346.18.

Example 6

N′-Ethyl-N-cyanourea: To a 20° C. solution of sodium hydroxide (1.5 Maqueous, 50 mL, 75.02 mmol) was added cyanamide (8.5 g, 202.25 mmol)then ethyl isocyanate (4 mL, 50.56 mmol) was added in a dropwise fashionover 10 minutes. After stirring for 30 minutes, additional sodiumhydroxide (3M, 25 mL. 75.02 mmol) and ethyl isocyanate (4 mL, 50.56mmol) were added. The resulting solution was then aged for a minimum of30 minutes before using directly without isolation.

Example 7

4-(Pyridin-3-yl)-2-nitroaniline: To a solution of 4-bromo-2-nitroaniline(4.8 g, 22 mmol) in DME (100 mL) was added pyridine-3-boronic acid1,3-propanediol cyclic ester (4 g, 24 mmol), sodium bicarbonate (45 mL,1M), and tetrakis(triphenylphosphine)palladium (0.05 eq). The resultingmixture was heated at 90° C. for 8 hours then cooled to roomtemperature. The solids were collected, washed with water, 5% EtOAc inHexane and dried to afford the title compound (5 g). ¹H NMR (CDCl₃) δ8.8 (d, 1H), 8.55 (m, 1H), 8.35 (d, 1H), 7.85 (dd, 1H), 7.65 (dd, 1H),7.35 (m, 1H), 6.95 (d, 1H), 6.25 (br s, 2H).

Example 8

2-Bromo-6-nitro-4-pyridin-3-yl-phenylamine: To a solution of4-(pyridin-3-yl)-2-nitroaniline (1.3 g, 9 mmol) in HOAc (25 mL) wasadded bromine (1.58 g, 9.9 mmol) in HOAc (5 mL). The resulting mixturewas stirred at room temperature for one hour and then quenched withice-water. The solids were collected, washed with water and dried. Thesolids in EtOAc was then washed with NaOH (2N; 20 mL), water, brine andconcentrated in vacuo. The concentrate was purified by chromatography[Silica Gel, ethyl acetate:hexanes (1:1)] to afford the title compound(0.8 g). ¹H NMR (CDCl₃) δ 8.83 (d, 1H), 8.55 (m, 1H), 8.41 (d, 1H), 8.15(d, 1H), 7.96 (m, 1H), 7.41 (m, 1H), 6.80 (br s, 2H). (M+1) 294.

Example 9

2-Nitro-6-pyridin-2-yl-4-pyridin-3-yl-phenylamine: A mixture of2-bromo-6-nitro-4-pyridin-3-yl-phenylamine (100 mg, 1 eq), 2-pyridylzincbromide (6 eq) and tetrakis(triphenylphosphine)palladium (0.1 eq) in THF(10 mL) was heated at 100° C. for 18 hours. The reaction was quenchedwith water (2 mL). The product was extracted with EtOAc (20×3). Thecombined organic layer was then concentrated in vacuo and the residuewas purified by chromatography (Silica Gel, EtOAC) to afford the titlecompound (75 mg) as a yellow solid. (M+1) 293.

Example 10

3-Pyridin-2-yl-5-pyridin-3-yl-benzene-1,2-diamine: To a solution of2-nitro-6-pyridin-2-yl-4-pyridin-3-yl-phenylamine (75 mg, 0.26 mmol) inethyl acetate (20 mL) was added 10% palladium on carbon (50 mg). Theresulting suspension was placed in a Parr hydrogenation apparatus under40 psi hydrogen gas while shaking at ambient temperature for one hour.The catalyst was removed by filtration and the filtrate concentrated invacuo to afford compound the title compound (50 mg, 0.19 mmol).

Example 11

1-Ethyl-3-(7-pyridin-2-yl-5-pyridin-3-yl-1H-benzoimidazol-2-yl)-urea(I-31): To a solution 3-pyridin-2-yl-5-pyridin-3-yl-benzene-1,2-diamine(50 mg, 0.19 mmol) and sulfuric acid (0.76 mL, 1 N) in water (1 mL) wasadded N′-ethyl-N-cyanourea (0.76 mL, 1 M). Enough sulfuric acid wasadded dropwise to achieve pH 3. The resulting mixture was heated at 100°C. for 8 hours. The reaction mixture was then cooled to ambienttemperature. The solids were collected, washed with water and dried. Thesolids were purified by chromatography (Silica Gel, EtOAc, then 10% MeOHin EtOAc) to afford compound 5 (27 mg). ¹H NMR (CDCl₃) δ 8.92 (d, 1H),8.80 (m, 1H), 8.52 (m, 1H), 8.30 (m, 1H), 8.21 (d, 1H), 8.04 (s, 1H),7.94 (m, 1H), 7.75 (s, 1H), 7.56 (d, 1H), 7.37 (m, 2H), 3.36 (q, 2H),1.24 (t, 3H). (M+1) 359.

Example 12

2,2-Dimethyl-N-(2-pyrimidin-2-yl-phenyl)-propionamide: A 5 L flask wascharged with the above depicted boronic acid as a tetrahydrate (281.4grams, 960 mmoles), 2-chloropyrimidine (100 g, 874 mmoles), NaHCO₃(146.8 grams, 1.746 moles), and Pd(PPh₃)₄ (10.0 grams, 8.72 mmoles).Water (1 L) and dimethoxyethane (1 L) were added, and the mixture washeated slowly to 83° C. (internal temperature) over a 1 hour period withoverhead stirring. After ˜2 hours all solids had dissolved. The reactionwas allowed to stir for 8 hours. The mixture was cooled to roomtemperature and stirred overnight after which time a thick precipitatehad formed. The crude mixture was diluted with water (2 L) and stirredfor an additional 2 hours after which time the mixture was filtered andthe solids were washed sequentially with water, 0.1 N NaOH, and wateragain. The solids were then dried under high vacuum at 50° C. to affordthe title compound (˜233 grams) as a tan powder.

Example 13

N-(4-Bromo-2-pyrimidin-2-yl-phenyl)-2,2-dimethyl-propionamide: To a roomtemperature suspension of2,2-dimethyl-N-(2-pyrimidin-2-yl-phenyl)-propionamide (˜117 grams, 437mmoles) in acetic acid (1 L) was added bromine (67 mL, 1.31 moles) as asolution in 100 mL of acetic acid over a 1 hour period. The heterogenousmixture was stirred at room temperature for 5 hours over which time athick precipitate formed. The mixture was then poured over ice, dilutedwith 1N Na₂S₂O₃ (2 L), and stirred for 1 hour. The solids were filtered,resuspended in water (2 L), stirred for 1 hour, then filtered and washedwith water again. The resulting solids were pumped to dryness at 50° C.,resuspended in HOAc (1 L), and treated with bromine (22 mL, 430 mmoles)in acetic acid solution (20 mL) over a 20 minute period. The resultingheterogenous mixture was stirred for 5 hours, then quenched and treatedas described above. The resulting solids were vacuum dried at 50° C. toafford the title compound (165 grams) as a tan powder.

Example 14

N-(4-Bromo-2-nitro-6-pyrimidin-2-yl-phenyl)-2,2-dimethyl-propionamide:To a 5° C. suspension ofN-(4-bromo-2-pyrimidin-2-yl-phenyl)-2,2-dimethyl-propionamide (32.6grams, 97.5 mmoles) in TFA (400 mL) was added 90% nitric acid (70 mL,1.46 mmoles) over a 30 minute period. The mixture was then allowed towarm to room temperature and stir for a total of 2 hours. The crudereaction (now homogenous) was poured into ice producing a pasty mass.The mixture was diluted to 2 L total volume with water, treated with 500mL of methanol, and vigorously stirred for 12 hours. The resultingsolids were filtered, washed with copious amounts of water, then vacuumdried at 50° C. to afford the title compound (29.9 grams, 81% yield) asa tan powder.

Example 15

4-Bromo-2-nitro-6-pyrimidin-2-yl-phenylamine: A suspension ofN-(4-bromo-2-nitro-6-pyrimidin-2-yl-phenyl)-2,2-dimethyl-propionamide(29.9 grams, 78.8 mmoles) in conc. HCl (200 mL) was refluxed for 8hours. The partially homogeneous crude reaction was then cooled to roomtemperature, diluted with water (500 mL), and the resulting precipitatewas stirred for 1 hour. The solids were then filtered, washed withwater, and vacuum dried at 50° C. to afford the title compound (21.1grams, 91% yield) as an orange powder.

Example 16

2-Nitro-6-pyrimidin-2-yl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine:A mixture of 4-bromo-2-nitro-6-pyrimidin-2-yl-phenylamine (1.82 g, 6.2mmol), bis(pinacolato)diboron (3.144 g, 12.4 mmol), PdCl₂dppf₂ (453 mg,0.6 mmol) and KOAc (3.03 g, 31 mmol) in dioxane (60 ml) was heated at105° C. for 2.5 hours. The reaction was filtered and washed withdichloromethane. The combined filtrates were concentrated under vacuumand water (100 ml) was added to the residue. Extraction withdichloromethane (3×50 ml), drying and concentration gave a residue,which was washed with ether-hexane to afford the title compound (2.07 g,98%).

Example 17

N-[2-(3-Fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide: A 3 Lflask was charged with the above depicted boronic acid as a tetrahydrate(92.1 grams, 314 mmoles), chlorofluoropyridine (37.6 g, 286 mmoles),NaHCO₃ (48.0 grams, 572 mmoles), and Pd(PPh₃)₄ (3.3 grams, 2.86 mmoles).Water (300 mL) and dimethoxyethane (300 mL) were added, and the mixturewas heated slowly to 83° C. (internal temperature) over a 1 hour periodwith overhead stirring. After ˜2 hours all solids had dissolved. Thereaction was allowed to stir for 10 hours. The mixture was cooled toroom temperature and stirred overnight after which time a thick gum hadformed. The crude mixture was diluted with water (2 L) and stirred foran additional 2 hours. The mixture was then allowed to rest withoutstirring until the gum had settled to the bottom of the flask. Theliquid phase was removed via vacuum, then replaced with 0.1 N NaOH andstirred for 15 minutes. The gum was allowed to settle and the liquidremoved via vacuum. The gum was then similarly washed three times withwater, then transferred to a 1 neck flask as an acetone solution. Themixture was concentrated in vacuo and azeotroped five times with ethylacetate.

Example 18

N-[4-Bromo-2-(3-fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide:To a room temperature suspension of N-[2-(3-fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide (˜77 mmoles) in aceticacid (300 mL) was added bromine (12 mL, 228 mmoles) as a solution in 50mL of acetic acid over a 1 hour period. The heterogenous mixture wasstirred at room temperature for 5 hours over which time a thickprecipitate formed. The mixture was then poured over ice, diluted with1N Na₂S₂O₃ (500 mL), and stirred for 1 hour. The solids were filtered,re-suspended in water (2 L), stirred for 1 hour, then filtered andwashed with water again. The resulting solids were pumped to dryness at50° C., re-suspended in HOAc (400 mL), and treated with bromine (4 mL,76 mmoles) in acetic acid solution (20 mL) over a 20 minute period. Theresulting heterogenous mixture was stirred for 5 hours, then quenchedand treated as described above. The resulting solids were vacuum driedat 50° C. to afford the title compound (19.1 grams, 72%) as a tanpowder.

Example 19

N-[4-Bromo-2-(3-fluoro-pyridin-2-yl)-6-nitro-phenyl]-2,2-dimethyl-propionamide:To a suspension ofN-[4-bromo-2-(3-fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide(6.45 grams, 18.4 mmoles) in TFA (100 mL) and TFAA (25.5 mL, 183.6mmole), at 0° C., was added a TFA solution (30 mL) of 90% fuming nitricacid (2.46 mL, 55.1 mmoles) over a 45 minute period. The mixture wasthen stirred at 0° C. for a total of 4 hours. The crude reaction (nowhomogenous) was poured into ice producing a pasty mass. The mixture wasdiluted to 500 mL total volume with water, treated with 50 mL ofmethanol, and vigorously stirred for 12 hours. The resulting solids werefiltered, washed with copious amounts of water, then dried in vacuo at50° C. to afford the title compound (6.1 grams, 82% yield) as a tanpowder.

Example 20

2-(3,5-Difluoro-phenyl)-pyrimidine: A solution of the difluoroboronicacid (5.4 g, 34.1 mmoles) and 2-chloropyrimidine (3.0 g, 26.2 mmoles) inethanol (50 mL) was treated with Na₂CO₃ (3.6 g, 34.1 mmoles) andPd(PPh₃)₄ (1.5 g, 1.31 mmoles) then heated at reflux for 3 days. Theresulting mixture was then diluted with EtOAc, Silica gel added, and theresulting slurry stirred for 3 hours at room temperature. The crudemixture was then filtered through a silica gel pad with EtOAc,concentrated in vacuo, and flash chromatographed (silica gel,19/1-14/1-9/1-7/1 hexanes/EtOAc gradient) to afford the title compound(1.38 g, 27%) as a white solid. ¹H NMR (dmso-d₆, 500 MHz): 8.95 (d, 2H);7.98 (m, 2H); 7.57 (dd, 1H); 7.48 (m, 1H).

Example 21

2-(3,5-Difluoro-2-nitro-phenyl)-pyrimidine: To a room temperaturesolution of 2-(3,5-difluoro-phenyl)-pyrimidine (1.2 g, 6.24 mmole) inH₂SO₄ (3 mL) was added 90% HNO₃ (0.375 mL, 9.37 mmoles) over 10 secondsvia syringe. The resulting mixture was stirred at room temperature for 1hour then poured into ice. The resulting heterogeneous mixture was thendiluted with water, warmed to room temperature, and filtered. The solidswere washed with water and dried in vacuo to afford the title compound(1.53 g, 100%) as a tan solid. ¹H NMR (dmso-d₆, 500 MHz): 8.92 (d, 2H);8.67 (m, 1H); 7.94 (m, 1H); 7.65 (dd, 1H).

Example 22

5-Fluoro-2-nitro-3-pyrimidin-2-yl-phenylamine: To a solution of2-(3,5-difluoro-2-nitro-phenyl)-pyrimidine (1.5 g, 6.32 mmoles) indioxane (10 mL) was added tBuNH₂ (6.6 mL, 63.24 mmoles) at roomtemperature. The mixture was heated to 100° C. in a sealed tube for 10hours. The mixture was then cooled to room temperature, poured intowater, and the solids stirred for 1 hour. The mixture was filtered,solids washed with water until filtrate was clear. The crude product wasthen diluted in MeOH, 6N HCl added, and the resulting mixture heated atreflux for 3 hours. The reaction was cooled to room temperature andpoured into ice. The resulting heterogeneous mixture was warmed to roomtemperature, filtered, solids washed with water until filtrate ranclear, and dried in vacuo to afford the title compound (1.33 g, 90%) asan orange powder. ¹H NMR (dmso-d₆, 500 MHz): 8.87 (d, 2H); 7.52 (dd,1H); 7.08 (dd, 1H); 6.86 (dd, 1H); 6.60 (s, 2H).

Example 23

1-(3-Amino-4-nitro-5-pyrimidin-2-yl-phenyl)-1H-imidazole-4-carboxylicacid cyclopropylamide: To a mixture of5-fluoro-2-nitro-3-pyrimidin-2-yl-phenylamine (650 mg, 2.77 mmole) inDMF (5 mL) was added 17 (545 mg, 3.6 mmoles) and Na₂CO₃ (381 mg, 3.60mmoles) at room temperature. The resulting mixture was heated to 125° C.for 6 hours, then cooled to room temperature. The resulting mixture wasdiluted with water and the yellow precipitate was stirred for 1 hour.The crude reaction was filtered and the solids washed with water untilthe filtrate ran clear. The washed solids were then dried in vacuo toafford the title compound (960 mg, 95%) as a yellow powder. ¹H NMR(dmso-d₆, 500 MHz): 8.91 (d, 1H); 8.42 (s, 1H); 8.29 (s, 1H); 8.08 (d,1H); 7.52 (dd, 1H); 7.36 (d, 1H); 7.29 (d, 1H); 6.59 (s, 2H); 2.89 (m,1H); 0.072 (m, 2H); 0.64 (m, 2H).

Example 24

N,N-Diethlycarboxy-2-methyl-2-thiopseudourea: To a mixture of2-methyl-2-thiopseudourea sulfate (22.8 g, 81.9 mmol) in methylenechloride (200 mL) was added triethylamine (34.5 mL, 245.7 mmol) andethyl chloroformate (20.65 g, 245 mmol). After stirring over night themixture was washed with water, brine then dried over sodium sulfate,filtered and concentrated in vacuo to a pungent oil which was flashchromatographed (10% ethyl acetate/hexanes) to provide the titlecompound (16.68 g, 86.9% Y) as a colorless oil which solidified onstanding. ¹H NMR (500 Mhz, CDCl₃) ∂1.3 (q, 6H), 2.41 (s, 3H), 4.22 (m,4H).

Example 25

N,N-Diethlyureamido-2-methyl-2-thiopseudourea: To a mixture of2-methyl-2-thiopseudourea sulfate (2.0 g, 7.18 mmol) in water (3 mL) wasadded ethyl isocyanate (1.137 mL, 14.37 mmol) followed by dropwise 6NNaOH to a stable pH 8. After 1 hour at pH8 the biphasic solution wasdiluted with aqueous saturated sodium bicarbonate and extracted intoethyl acetate (3×100 mL). The combined organic layers were washed withbrine and dried over sodium sulfate, filtered then concentrated in vacuoto afford the title compound as a pungent oil (1.54 g, 92.7%). TLC (50%Ethyl acetate/methylene chloride) and ¹H NMR suggests that the materialis a mixture of mono and diacyl pseudourea. ¹H NMR (500 Mhz, CDCl₃)∂1.18 (m 2, 6H), 2.31 and 2.41 (2s, 3H), 3.28 (m, 4H).

Example 26

[5-(4-Cyclopropylcarbamoyl-imidazol-1-yl)-7-pyrimidin-2-yl-1H-benzoimidazol-2-yl]-carbamicacid ethyl ester: To a solution of1-(3-amino-4-nitro-5-pyrimidin-2-yl-phenyl)-1H-imidazole-4-carboxylicacid cyclopropylamide (65 mg, 0.178 mmoles) in MeOH (10 mL) was addedRa—Ni (2 drops of water slurry, catalytic) and the resulting suspensionwas placed under 45 psi of H₂ (Parr shaker) for 2 hours. The resultingmixture was then filtered, concentrated, diluted with 3 mL of pH=3.5buffer (made from 1M H₂SO₄ with enough NaOAc to raise pH to 3.5), andtreated with N,N-diethlycarboxy-2-methyl-2-thiopseudourea (0.267 mL of a1M solution of N,N-diethlycarboxy-2-methyl-2-thiopseudourea in dioxane)at room temperature. The resulting mixture was refluxed for 5 hoursresulting in a heterogeneous suspension. The reaction was cooled to roomtemperature, diluted with water and enough NH₄OH to raise the pH to˜6.0. The solids were then filtered and washed sequentially with water,2/1 water/ethanol, EtOAc, and then hexanes. The resulting solids weresuspended in MeOH, 2 equivalents of methanesulfonic acid was added, andconcentrated in vacuo to afford the title compound (75, 70%) as anoff-white solid. ¹H NMR (dmso-d₆, 500 MHz): 9.28 (s, 1H); 9.08 (d, 1H);8.8-7.4 (v. broad s, 4H); 8.67 (s, 1H); 8.53 (s, 1H); 8.46 (d, 1H); 8.05(d, 1H); 7.59 (dd, 1H); 4.33 (q, 2H); 2.88 (m, 1H); 2.35 (s, 6H); 1.34(t, 3H); 0.76 (m, 2H); 0.61 (m, 2H).

Example 27

We have prepared other compounds of formula I by methods substantiallysimilar to those described in Schemes I through IV, Examples 1 through26, and by methods known in the art. The characterization data for thesecompounds is summarized in Table 3 below and includes LC/MS (observed)and ¹H NMR data.

¹H NMR data is summarized in Table 3 below wherein ¹H NMR data wasobtained at 500 MHz in deuterated DMSO, unless otherwise indicated, andwas found to be consistent with structure. Compound numbers correspondto the compound numbers listed in Table 2.

TABLE 3 Characterization Data for Selected Compounds of Formula I M − 1M + 1 Compound No. I- (obs) (obs) ¹H NMR 16 347.2 349.2 1.1 (t, 3H) 3.2(q, 2H) 6.8 (t, 1H) 7.5 (m, 1H), 7.7 (s, 1H) 7.9 (s, 1H) 8.1 (d, 1H) 8.3(s, 1H) 8.6 (d, 1H) 8.9 (s, 1H)9.6 (s1H) 10.3 (s, 1H) 20 360.3 362.3(CD₃OD): 8.89 (dd, 1H); 8.51 (dd, 1H); 8.42-8.29 (br. s, 1H), 8.18 (ddd,1H); 7.94-7.77 (br. s, 1H); 7.63 (br. s); 7.58 (br. s, 1H); 7.53 (dd,1H); 3.32 (q, 2H); 2.21 (s, 3H); 1.23 (t, 3H) 24 391.3 393.3 1.13 (t,3H), 1.3 (t, 3H) 3.24 (q, 2H), 3.37 (q, 2H), 7.82 (s, 1H), 7.82 (s1H),7.96 (t, 1H)8.19 (s, 1H), 8.56 (s, 1H), 8.62 (d, 1H), 8.82 (d, 1H), 9.15(s, 1H), 11.02 (s, 1H) 42 390.3 392.2 1.13 (t, 3H) 2.45 (s, 3H) 3.23 (q,2H) 3.46 (s, 3H) 6.58 (m, 4H), 7.78 (m, 3H) 9.11 (s, 1H) 10.51 (s, 1H)12.18 (s, 1H) 43 — — 1.15 (t, 3H), 3.25 (m, 2H), 3.35 (s, 3H), 4.6 (s,2H), 7.4 (br s, 1H), 7.55 (s, 1H), 7.8 (m, 1H), 8.0 (d, 1H), 8.05 (d,1H), 8.6 (m, 1H), 8.7 (m, 1H), 9.2 (s, 1H), 10.4 (br s, 1H) 49 — — 1.3(t, 3H), 4.3 (q, 2H), 6.65 (t, 1H), 7.75 (d, 1H), 7.85 (dd, 1H), 7.9 (s,1H), 8.05 (d, 1H), 8.5 (d, 1H), 8.75 (dd, 1H), 9.1 (s, 1H0, 11.7 (br s,1H), 50 377.2 379.1 1.23 (t, 3H), 2.89 (s, 3H), 3.36 (q, 2H), 7.93 (d,1H), 8.16 (d, 1H), 8.26 (d, 1H), 8.33 (d, 1H), 8.86 (d, 1H), 8.97 (d,1H), 9.30 (d, 1H) 51 — — 1.1 (t, 3H), 1.25 (t, 3H), 3.25 (q, 2H), 3.37(s, 3H), 4.05 (q, 2H), 6.6 (m, 4H), 7.65 (s, 1H), 7.9 (m, 2H) 9.1 (br s,1H), 10.2 (br s, 1H), 11.8 (br s, 1H) 54 — — 0.5 (m, 2H), 0.8 (m, 2H),2.7 (m, 1H), 6.4 (br s, 1H), 6.7 (m, 1H), 7.75 (s, 1H), 7.8 (m, 1H),7.85 (s, 1H), 8.05 (m, 1H), 8.5 (brs, 1H), 8.7 (m, 1H), 9.05 (s, 1H),9.15 (s, 1H), 10.2 (br s, 1H) 55 — — 1.15 (t, 3H), 3.25 (m, 2H), 7.25(m, 1H), 7.5 (br s, 1H), 7.7 (m, 1H), 7.85 (s, 1H), 8.3 (s, 1H), 8.4 (m,1H), 8.7 (m, 2H), 8.85 (s, 1H), 9.1 (s, 1H), 9.15 (dd, 1H), 10.5 (br s,1H), 57 377.1 379.2 9.08 (d, 1H); 8.48 (br. s, 1h); 8.13, (d, 1H); 7.95(d, 1H); 7.88 (s, 1H); 7.25 (d, 1H); 6.75 (d, 1H); 6.64 (s, 1H);, 6.62(dd, 1H); 6.4-5.7 (br. s, 2H); 5.69 (q, 2H); 3.48 (s, 3H); 1.48 (t, 3H)61 — — 1.13 (t, 3H) 2.38 (s, 3H) 3.24 (q, 2H) 5.36 (s, 2H) 6.71 (m, 2H),6.83 (s, 1H) 7.18 (d, 2H) 7.28 (t, 1H) 7.38 (m, 2H) 7.76 (s, 1H) 7.92(s, 2H), 8.30 (s, 1H) 9.08 (s, 1H) 11.50 (s, 1H) 62 404.3 406.3 12.15,11.81 (s, 1H), 10.34, 9.99 (s, 1H), 9.13, 8.99 (s, 1H), 7.99-7.81 (m,3H), 7.68 (s, 1H), 7.30-6.59 (m, 4H), 5.09 (m, 1H), 3.23 (t, 2H), 1.33 9(d, 6H), 1.13 (t, 3H) 63 — — 1.15 (t, 3H) 2.44 (s, 3H) 3.25 (q, 2H) 5.44(s, 2H) 6.70 (m, 3H), 7.40 (d, 1H) 7.49 (t, 1H) 7.75 (s, 1H) 7.85 (m,1H) 7.97 (s, 2H) 8.12 (s, 1H), 8.60 (d, 1H) 9.09 (s, 1H) 11.21 (s, 1H)64 — — 1.2 (t, 3H), 2.2 (m, 2H), 3.3 (m, 2H), 3.65 (m, 2H), 4.1 (t, 2H),7.75 (s, 1H), 7.84 (s, 1H), 7.87 (s, 1H), 7.8 (m, 1H0, 8.5 (m, 1H), 8.65(m, 1H), 9.0 (s, 1H) 65 423.1 425.1 (MeOH-d₄& CDCl₃): 8.30-7.85 (m, 4H),6.78 (s, 1H), 6.58 (s, 1H), 3.60 (s, 3H), 3.37 (q, 2H), 2.80 (s, 3H),1.25 (t, 3H) 67 — — 1.15 (t, 6H), 3.45 (q, 4H), 6.7 (s, 1H), 7.7 (m,2H), 7.9 (s, 1H), 8.1 (s, 1H), 8.4 (m, 1H), 8.7 (m, 1H), 9.1 (m, 2H),10.6 (br s, 1H), 68 453.2 455.2 12.17, 11.81 (s, 1H), 10.35, 9.99 (s,1H), 9.13, 9.00 (s, 1H), 8.52 (s, 1H), 7.99-7.69 (m, 5H), 7.32-7.27 (m,2H), 6.93-6.59 (m, 4H), 5.23 (s, 2H), 3.22 (q, 2H), 1.13 (t, 3H) 69407.3 409.2 (MeOH-d₄, HCl salt)): 8.62 (s, 1H), 7.96-7.93 (m, 2H), 7.59(s, 1H), 6.67 (s, 1H), 5.81 (s, 1H), 3.45, 3.39 (s, 3H), 3.36 (q, 2H),3.28, 3.20 (s, 3H), 1.23 (t, 3H) 70 — — 1.15 (t, 3H), 1.35 (t, 3H), 3.25(q, 2H), 4.3 (q, 2H), 7.1 (br s, 1H), 7.85 (s, 1H), 8.05 (m, 1H), 8.2(s, 1H), 8.3 (s, 1H), 8.8 (m, 1H), 8.85 (d, 1H), 9.25 (s, 1H0, 9.65 (s,1H), 10.7 (br s, 1H), 71 416.2 418.2 0.84 (m, 2H) 1.14 (m, 5H) 2.55 (s,3H) 2.91 (m, 1H) 3.26 (q, 2H), 6.59 (s, 1H) 6.65 (s, 1H) 6.69 (s, 1H)7.65 (s, 1H) 7.81 (m, 1H) 7.97 (s, 1H), 8.07 (s, 1H) 9.07 (s, 1H) 11.59(s, 1H) 72 — — 1.1 (t, 3H), 3.2 (q, 2H), 7.1 (br s, 1H), 7.8 (s, 1H),8.0 (m, 1H), 8.2 (s, 1H), 8.25 (s, 1H), 8.7 (m, 1H), 8.8 (m, 1H), 9.2(s, 1H), 9.6 (s, 1H), 10.7 (br s, 1H), 73 448.2 450.2 (CD₃OD): 1.18-1.26(m, 9H), 3.27 (s, 3H), 3.36 (q, 2H), 4.21 (s, 2H), 6.65-6.68 (m, 1H),6.90-6.94 (m, 1H), 6.98-7.01 (m, 1H), 7.78-7.84 (m, 2H), 7.93-7.96 (m,1H), 8.09-8.11 (m, 1H), 8.74-8.76 (m, 1H) 74 434.3 436.3 (CD₃OD):1.21-1.27 (m, 9H), 3.36 (q, 2H), 4.17 (s, 2H), 6.65-6.68 (m, 1H),6.95-6.99 (m, 1H), 7.00-7.03 (m, 1H), 7.79-7.82 (m, 1H), 7.89 (d, 1H),7.94-7.96 (m, 1H), 8.09-8.11 (m, 1H), 8.73-8.76 (m, 1H) 75 — — 1.1 (t,3H), 3.0 (br s, 3H), 3.25 (m, 5H), 7.0 (br s, 1H), 7.75 (m, 2H), 8.05(s, 1H), 8.15 (s, 1H), 8.45 (m, 1H), 8.7 (m, 1H), 9.1 (s, 1H), 9.4 (s,1H), 10.4 (br s, 1H), 77 448.3 450.2 (CD₃OD): d 1.24 (t, 3H), 1.27 (d,3H), 1.47 (d, 3H), 3.36 (q, 2H), 3.37 (s, 3H), 3.58-3.67 (m, 1H),5.21-5.28 (m, 1H), 6.68-6.71 (m, 1H), 7.80 (d, 1H), 7.85 (s, 1H),7.95-7.99 (m, 2H), 8.27 (s, 1H), 8.38 (d, 1H), 8.78-8.82 (m, 1H). 78448.3 450.3 (CD₃OD): d 1.24 (t, 3H), 1.31 (d, 3H), 1.51 (d, 3H), 3.38(q, 2H), 3.42 (s, 3H), 3.66-3.73 (m, 1H), 5.44-5.51 (m, 1H), 6.68-6.71(m, 1H), 7.94 (d, 1H), 7.96-7.98 (m, 1H), 8.03 (s, 1H), 8.07 (s, 1H),8.32 (s, 1H), 8.43 (d, 1H), 8.81-8.86 (m, 1H). 79 434.3 436.2 (CD₃OD): d1.24 (t, 3H), 1.32 (d, 3H), 1.50 (d, 3H), 3.37 (q, 2H), 3.93-4.02 (m,1H), 5.14-5.22 (m, 1H), 6.67-6.71 (m, 1H), 7.90 (d, 1H), 7.95-7.98 (m,1H), 8.02 (s, 1H), 8.04 (s, 1H), 8.32 (s, 1H), 8.41 (d, 1H), 8.81-8.85(m, 1H). 82 428.2 430.1 9.0 (m, 1H), 8.6 (d, 1H), 8.4 (m, 1H), 8.1-8.2(m, 2H), 8.0 (m, 1H), 7.8 (m, 1H), 7.5 (m, 2H), 6.6 (s, 1H), 4.8 (s,1H), 2.55 (s, 3H), 3.25 (m, 2H), 2.1 (s, 3H), 1.1 (t, 3H) 83 417.1 419.111.01 (br. s, 1H); 9.10 (d, 1H); 8.37, (s, 1H); 8.19 (s, 1H); 7.97 (s,1H); 7.78 (br. s, 1H); 7.58 (m, 1H); 7.08, (s, 1H); 6.68 (m, 1H); 3.88(dd, 2H); 3.22 (dq, 2H); 2.99 (dd, 2H);, 1.91 (ddd, 2H); 1.85 (ddd, 2H);1.11 (t, 3H). 84 377.2 379.2 (MeOD-d₃): 8.72 (br s, 1H), 8.58 (s, 1H),8.40 (s, 1H), 8.19 (s, 1H), 7.95 (s, 1H), 7.14 (s, 1H), 6.68 (s, 1H),3.60 (s, 3H), 3.21 (q, 2H), 1.24 (t, 3H). 85 430.2 432.2 (MeOD-d₃,salt): 8.64 (d, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.97 (d, 1H), 7.64 (s,1H), 6.66 (dd, 1H), 6.51 (s, 1H), 3.89 (s, 3H), 3.48 (s, 3H), 3.37 (q,2H), 1.24 (t, 3H) 87 360.1 362.1 MeOD-d₃, 1.24 (t, 3H), 2.42 (s, 3H),3.38 (q, 2H), 6.87 (s, 1H), 7.94 (s, 1H), 8.15 (m, 2H), 8.85 (d, 1H),8.98 (d, 1H), 9.30 (s, 1H) 88 388 390 9.27 (s, 2H). 9.20 (s, 1H), 8.27(s, 1H). 8.10 (m, 1H), 7.94 (s, H), 7.92 (d, 1H), 6.95 (d, 1H), 4.10 (s,3H), 3.25 (m, 2H), 1.11 (t, 3H) 89 386.9 389.2 (CD₃OD) 8.92-6.96 (m,9ArH), 3.99 (s, 3H), 3.36 (q, 2H), 1.24 (t, 3H) 90 457.1 459.2 — 91429.2 431.2 (CD₃OD): 8.97 (s, 1H); 8.89 (d, 1H); 8.49 (d, 1H); 8.37 (m,2H); 8.22 (ddd, 1H); 7.93 (d, 1H); 7.64 (dd, 1H); 3.38 (q, 2H); 2.91 (m,1H); 1.25 (t, H): 0.88 (m, 2H); 0.67 (m, 2H). 92 360.13 362.19 1.15 (t,3H), 3.25 (m, 2H), 3.9 (s, 3H), 7.15 (m, 1H), 7.65 (m, 1H), 7.8 (s, 1H),8.0 (s, 1H), 8.2 (m, 1H), 8.3 (m, 1H), 8.65 (m, 1H), 9.0 (m, 2H), 10.3(br s, 1H) 93 371 373 1.12 (t, 3H), 3.25 (m, 2H), 4.2 (bs, 2H),7.0.2-7.25 (m, 1H), 7.5 (m, 1H), 7.81 (m, 1H), 8.08 (t, 1H), 8.22 (m,1H), 8.61-8.48 (m, 2H), 8.4 (d, 1H), 8.46 (s, 1H). 94 430 432 0.92 (d,6H), 1.12 (m, 3H), 2.23 (m.1H), 2.83 (d, 2H), 3.35 (m, 2H), 7.5 (m, 1H),7.61 (bs, 1H), 7.89 (s, 1H), 8.1 (m, 1H), 8.4 (s, 1H), 8.58 (m, 1H),8.78 (bs, 1H), 8.3 (d, 1H). 95 431.03 433.2 (CD₃OD) 1.2 (7, 3H), 3.3 (q,2H), 3.8 (m, 2H), 4.6 (m, 2H), 7.4 (m, 1H), 7.8 (m, 1H), 8.0 (s, 1H),8.3 (m, 2H), 8.5 (m, 1H), 8.7 (m, 2H), 9.1 (s, 1H) 96 507.2 509.2(CD₃OD): 8.9 (d, 1H), 8.55 (d, 1H), 8.4 (s, 1H), 8.3 (m, 1H), 8.0 (s,1H), 7.7 (m, 1H), 7.3 (t, 1H), 7.0 (s, 2H), 6.85 (d, 1H), 6.7 (d, 2H),5.5 (s, 2H), 3.7 (s, 3H), 3.3 (q, 2H), 2.5 (s, 3H), 1.25 (t, 3H) 97 401403 9.1 (s, 1H), 8.6 (d, 2H), 8.3 (m, 1H), 8.1 (s, 1H), 7.9 (s, 1H), 7.8(s, 1H) 7.5 (m, 1H), 7.0 (d, 1H), 4.3 (m, 2H), 3.3 (m, 2H), 1.4 (t, 3H),1.1 (t, 3H). 98 497.03 499.18 , 1.16 (t, 3H) 3.25 (q, 2H) 4.44 (d, 2H)7.17 (t, 2H) 7.38 (t, 2H)7.53 (t, 1H) 7.79 (m, 1H) 7.87 (s, 1H) 8.10 (t,1H) 8.32 (s, 1H)8.51 (s, 1H) 8.57 (d, 1H) 8.77 (s, 1H) 8.82 (d, 1H) 8.94(t, 1H)11.10 (br s, 1H) 99 432 434 — 100 418.25 420.15 1.1 (t, 3H), 3.2(m, 2H), 3.95 (s, 3H), 4.1 (s, 2H), 7.2 (br s, 1H), 7.25 (brs, 1H), 7.9(s, 1H), 8.2 (m, 1H), 8.25 (s, 1H), 8.7 (d, 1H), 9.05 (s, 2H), 10.4 (brs, 1H) 101 431 433 8.65 (d, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 7.98 (d,1H), 7.78 (d, 1H), 7.38 (m, 1H), 6.93 (s, 1H), 6.89 (dd, 1H), 4.51 (q,2H), 3.63 (s, 3H), 3.35 (q, 2H), 1.55 (t, 3H), 1.22 (t, 3H) 102 375 3778.86 (d, 1H), 8.69 (m, 1H), 8.52 (d, 1H), 8.16 (m, 2H), 7.79 (m, 2H),7.56 (m, 1H), 7.50 (m, 1H), 3.55 (m, 2H)1.23, (t, 3H) 103 430 432.1 8.87(br. s, 1H); 8.81 (d, 1H); 8.66 (br. s., 1H); 8.49 (s, 1H); 8.39 (br.s., 1H); 8.25 (d, 1H); 8.09 (ddd, 1H); 7.87 (d, 1H); 7.52 (dd, 1H); 5.3(very br. s, 5H); 4.29 (q, 2H); 2.85 (m, 1H); 1.31 (t, 3H); 0.72 (m,2H); 0.63 (m, 104 417.19 419.14 1.1 (t, 3H), 3.2 (q, 2H), 3.45 (s, 3H),4.1 (s, 3H), 6.7 (dd, 1H), 6.85 (d, 1H), 7.15 (br s, 1H), 7.35 (br s,1H), 7.8 (d, 1H), 7.95 (s, 1H), 8.2 (s, 1H), 8.4 (br s, 1H), 8.7 (d,1H), 10.5 (br s, 1H) 105 406 408 8.97 (br. s, 2H); 8.60 (d, 1H); 7.99(br. s., 1H); 7.96 (m, 1H); 7.81 (br. s., 1H); 7.57 (m, 1H); 3.98 (s,3H); 3.25 (m, 2H); 1.11 (t, 3H). 106 508.2 510.2 1.1 (t, 3H), 2.4 (s,3H), 3.2 (q, 2H), 4.1 (s, 3H), 5.4 (s, 2H), 6.65 (s, 1H), 6.75 (s, 1H),7.15 (br s, 1H), 7.3 (m, 2H), 7.35 (m, 1H), 7.8 (m, 1H), 7.95 (s, 1H),8.25 (s, 1H), 8.35 (br s, 1H), 8.5 (m, 1H), 8.75 (m, 1H), 10.5 (br s,1H) 107 495.2 497.2 8.8 (m, 1H), 8.2 (m, 1H), 7.9 (s, 1H), 7.8 (m, 1H),7.4 (m, 2H), 7.35 (d, 2H), 7.25 (d, 2H), 6.7-6.8 (m, 2H), 5.3 (2, 2H),4.0 (m, 1H), 3.4 (q, 2H), 2.4 (s, 3H), 1.1 (t, 3H) 108 417 419 9.12 (br.s, 1H); 8.60 (d, 1H); 8.39 (m, 1H); 8.36 (s, 1H); 8.25 (s, 1H); 7.89 (s,1H); 7.70 (dd, 1H); 7.41 (m, 1H); 4.13 (s, 3H); 3.98 (s, 3H); 3.26 (m,2H); 1.15 (t, 3H). 109 358.3 360.1 (CD₃OD) 9.61 (d, 1H), 9.22 (d, 1H),8.83-8.79 (m, 3H), 8.65 (d, 1H), 8.47 (d, 1H), 8.02 (dd, 1H), 8.00 (s,1H), 3.37 (q, 2H), 1.24 (t, 3H) 110 388.3 390.2 (CDCl₃) 14.05 (br s,1H), 12.85 (br s, 1H), 8.37 (t, 1H), 7.97 (d, 1H), 7.88 (d, 1H),7.79-7.74 (m, 2H), 7.63 (dd, 1H), 7.46 (d, 1H), 6.62 (dd, 1H), 5.75 (brs, 1H), 3.45-3.40 (m, 2H), 1.27 (t, 3H) 111 492.3 494.1 10.3 (s, 1H),8.9 (d, 1H), 8.6 (m, 1H), 8.5 (d, 1H), 8.2 (s, 1H), 8.05 (t, 1H),7.8-7.9 (m, 2H), 7.5 (m, 2H), 7.4 (d, 1H), 7.3 (m, 1H), 6.7 (s, 1H), 6.6(s, 1H), 3.3 (q, 2H), 1.9 (d, 3H), 1.1-1.2 (t, 3H). 112 475.2 477.210.62 (s, 1H); 8.74 (d, 1H); 8.65 (s, 1H); 8.40 (s, 1H); 8.28 (s, 1H);8.23 (s, 1H); 7.87 (s, 1H); 7.43 (s, 1H); 7.32 (m, 2H); 5.52-4.41 (br.s, 3H); 4.10 (s, 3H); 3.24 (dt, 2H); 1.41 (s, 9H); 1.13 (t, 3H). 113494.2 496.2 (CD₃OD) 9.06 (s, 1H); 8.93 (d, 1H); 8.71 (d, 1H); 8.50 (m,2H); 8.39 (s, 1H); 8.00 (s, 1H); 7.87 (dd, 1H); 7.42 (d, 2H); 7.35 (dd,2H); 7.25 (dd, 1H); 5.27 (q, 1H); 4.41 (q, 2H); 1.62 (d, 3H); 1.42 (t,3H) 114 370.2 372.2 12.09 & 12.74 (s, 1H), 10.25 & 9.94 (s, 1H), 9.12 &8.94 (s, 1H), 8.35-6.58 (m, 9H), 3.24 (m, 2H), 1.13 (t, 3H) 115 442.1444.3 (CD₃OD) 8.65 (d, 1H), 7.94 (s, 1H), 7.91 (d, 1H), 7.72 (d, 2H),7.66 (s, 1H), 7.40 (d, 2H), 6.63 (dd, 1H), 4.52 (s, 2H), 3.40 (t, 2H),3.35 (q, 2H), 2.47 (t, 2H), 2.09-2.03 (m, 2H), 1.24 (t, 3H) 116 382 384— 117 415 417 9.17 (br. s, 1H); 9.0 (m, 1H); 8.98 (d, 1H); 8.72 (d, 1H);8.55 (m, 1H); 8.38 (s, 1H); 7.94 (s, 1H); 7.86 (d, 1H); 7.79 (m, 1H);3.97 (s, 3H); 3.27 (m, 2H); 1.15 (t, 3H). 118 401 403 — 119 403.3 405.2(CD₃OD): 8.78 (s, 1H), 8.67 (d, 1H), 8.37 (d, 1H), 8.24 (d, 1H), 8.22(s, 1H), 8.04 (d, 1H), 7.91 (s, 1H), 7.67 (dd, 1H), 7.40 (dd, 1H), 4.22(s, 3H), 3.34 (q, 2H), 1.23 (t, 3H) 120 434.32 436.23 1.1 (t, 3H), 2.8(s, 6H), 3.2 (m, 2H), 3.4 (s, 3H), 4.6 (s, 2H), 6.6 (d, 1H), 6.8 (s,1H), 7.2 (br s, 1H), 7.6 (s, 1H), 7.8 (d, 1H), 7.9 (s, 1H), 7.95 (s,1H), 10.0 (br s, 1H), 10.2 (br s, 1H) 121 414 416 (CD₃OD): 9.40 (br. s,1H); 9.07 (d, 1H); 8.98 (d, 1H); 8.91 (d, 1H); 8.80 (s, 1H); 8.60 (s,1H); 8.24 (dd, 1H); 8.11 (d, 1H); 7.84 (dd, 1H); 3.35 (m, 2H); 3.01 (s,3H); 1.25 (t, 3H). 122 415 417 — 123 435.28 437.26 1.3 (t, 3H), 2.8 (s,6H), 3.5 (s, 3H), 4.2 (q, 2H), 4.6 (s, 2H), 6.6 (dd, 1H), 6.7 (s, 1H),7.7 (s, 1H), 7.8 (d, 1H), 8.0 (m, 2H), 10.1 (br s, 1H), 11.7 (br s, 1H)124 431.2 433.2 9.28 (s, 1H); 9.08 (d, 1H); 8.8-7.4 (v. broad s, 4H);8.67 (s, 1H); 8.53 (s, 1H); 8.46 (d, 1H); 8.05 (d, 1H); 7.59 (dd, 1H);4.33 (q, 2H); 2.88 (m, 1H); 2.35 (s, 6H); 1.34 (t, 3H); 0.76 (m, 2H);0.61 (m, 2H). 125 447.4 — 9.10 (s, 1H); 8.60 (d, 1H); 8.47 (m, 2H); 7.95(s, 1H); 7.83 (s, 1H); 7.12 (d, 1H); 5.2-3.6 (br. m, 7H); 2.86 (m, 1H);1.30 (t, 3H); 0.75 (m, 2H); 0.64 (m, 2H) 126 439.2 441.2 (CDCl₃) 13.89(br s, 1H), 12.89 (br s, 1H), 8.28 (d, 1H), 8.25 (d, 1H), 7.96 (d, 1H),7.74 (s, 1H), 7.69-7.43 (m, 6H), 7.40 (s, 1H), 6.64 (dd, 1H), 6.11 (brs, 1H), 3.46-3.40 (m, 2H), 1.27 (t, 3H) 127 418.2 420.2 (CD₃OD) 9.72 (d,1H), 8.87 (d, 1H), 8.82 (d, 1H), 8.11 (d, 1H), 8.09 (d, 1H), 7.85 (d,1H), 7.39 (d, 1H), 7.36 (d, 1H), 4.43 (q, 2H), 3.35 (q, 2H), 1.44 (t,3H), 1.24 (t, 3H) 128 449.8 452.1 (CD₃OD) 9.21 (d, 1H), 8.83 (ddd, 1H),8.81 (dd, 1H), 8.68 (d, 1H), 8.26 (d, 1H), 8.18 (d, 1H), 8.07 (dd, 1H),8.05 (d, 1H), 7.50 (dd, 1H), 3.36 (q, 2H), 3.34 (s, 3H), 1.23 (t, 3H)129 — — 9.31 (s, 1H); 9.08 (d, 2H); 8.63 (s, 1H); 8.43 (d, 1H); 8.02 (d,1H); 7.89 (s, 1H); 7.57 (t, 1H); 8.8-6.6 (very br. s, 4H); 4.31 (q, 2H);2.32 (s, 6H); 1.42 (s, 9H); 1.33 (t, 3H). 130 495.4 497.2 9.07 (d, 2H);8.73 (d, 1H); 8.56 (s, 1H); 8.44 (d, 1H); 8.03 (d, 1H); 7.57 (t, 3H);7.44 (d, 2H); 7.36 (dd, 2H); 7.26 (dd, 1H); 6.95-5.90 (very broad s.,5H); 5.18 (dt, 1H); 4.32 (q, 2H); 2.32 (s, 6H); 1.53 (d, 3H); 1.33 (t,3H). 131 432 434 (CD₃OD) 1.08 (d, 6H), 1.43 (t, 3H), 2.33 (m, 1H), 2.91(d, 2H), 4.45 (q, 2H), 7.53 (t, 1H), 8.08 (s, 1H), 8.79 (s, 1H)<8.94 (s,1H), 9.05 (d, 2H), 9.5 (s, 1H). 132 514.23 516.23 8.84 (d, 1H),8.81-8.83 (m, 1H), 8.35 (s, 1H), 8.06 (dd, 1H), 7.90 (dd, 1H), 7.80 (d,1H), 6.80 (br s, 1H), 6.70 (d, 1H), 4.30 (q, 2H), 3.42-3.54 (m, 4H),3.48 (s, 3H), 3.12-3.17 (m, 4H), 2.81 (d, 3H), 1.32 (t, 3H) ppm 133501.33 503.26 — 134 521.6 523.2 (CD₃OD) 8.82 (s, 1H), m 8.46 (d, 1H),8.30 (s, 1H), 8.13 (dd, 1H), 7.90 (s, 1H), 7.55 (dd, 1H), 7.28 (dd, 1H),6.86-6.77 (m, 4H), 6.74 (s, 1H), 3.77 (s, 3H), 3.36 (q, 2H), 2.41 (br s,3H), 1.97 (d, 3H), 1.24 (t, 3H) 135 470.3 472.5 (CD₃OD) 8.85 (br s, 1H),8.45 (d, 1H), 8.34 (dd, 1H), 8/26 (dd, 1H), 8.13 (ddd, 1H), 7.96 (dd,1H), 7.56 (dd, 1H), 7.43 (dd, 1H), 7.29 & 7.20 (s, 1H), 5.49 (m, 1H),3.66-3.25 (m, 4H), 3.38 (q, 2H), 2.94 (2s, 3H), 2.52 (m, 1H), 2.38 (m,1H), 2.15 (m, 1H) 136 521.3 523.3 (CD₃OD) 8.81 (d, 1H), 8.43 (d, 1H),8.27 (s, 1H), 8.11 (ddd, 1H), 7.88 (s, 1H), 7.54 (dd, 1H), 7.28 (dd,1H), 6.87 (d, 1H), 6.84 (d, 1H), 6.81 (s, 1H), 4.42 (q, 2H), 3.78 (s,3H), 2.50 (br s, 3H), 2.00 (d, 3H), 1.41 (t, 3H) 137 522.6 524.2 (CD₃OD)8.90 (d, 1H), 8.81 (d, 1H), 8.49 (dd, 1H), 8.41 (s, 1H), 8.06 (s, 1H),7.84 (dd, 1H), 7.29 (dd, 1H), 6.99 (br s, 1H), 6.92 (s, 1H), 6.87 (d,1H), 6.84 (d, 1H), 6.81 (s, 1H), 4.42 (q, 2H), 3.78 (s, 3H), 2.50 (br s,3H), 2.00 (d, 3H), 1.41 (t, 3H) 138 525 527 1.2 (t.3H). 1.5 (d, 3H),3.73 (s, 3H), 4.3 (q, 2H), 5.13 (m, 1H), 6.8 (d, 1H), 7.0 (m, 2H), 7.24(t, 1H), 7.53 (t, 1H), 7.93 (s, 1H), 8.24 (s, 1H), 8.32 (m, 2H), 8.4 (s,1H), 9.08 (s, 1H), 11.79 (bs, 1H), 12.18 (s, 1H). 139 522.5 524.2(CD₃OD): 8.86 (d, 1H), 8.74 (d, 1H), 8.41 (dd, 1H), 8.35 (s, 1H), 7.99(s, 1H), 7.78 (dd, 1H), 7.28 (dd, 1H), 6.85 (d, 1H), 6.83 (d, 1H), 6.80(s, 2H), m 6.76 (s, 1H), 4.41 (q, 2H), 3.77 (s, 3H), 2.41 (br s, 3H),1.97 (d, 3H), 1.41 (t, 3H) 140 499 501 — 141 425.3 427.2 (CD₃OD) 8.8 (d,1H), 8.35 (d, 1H), 8.2 (s, 1H), 8.1 (t, 1H), 8.0 (s, 1H), 7.9 (d, 1H),7.8 (s, 1H), 7.65-7.7 (dd, 1H), 7.5 (t, 1H), 7.49 (d, 1H), 4.6 (s, 2H),4.45 (s, 1H), 3.4 (q, 2H), 3.2 (s, 3H), 3.15 (s, 1H), 1.2 (t, 3H) 142426.3 428.2 (CD₃OD): 8.8 (d, 1H), 8.6 (d, 1H), 8.3 (m, 2H), 8.1 (s, 1H),8.0 (d, 1H), 7.9 (s, 1H), 7.7 (d, 1H), 4.6 (s, 2H), 4.45 (s, 1H),4.4-4.5 (q, 2H), 3.3 (s, 3H), 3.15 (s, 1H), 1.4 (t, 3H) 143 498 500 —144 497 499 (CD₃OD) 1.42 (t, 3H), 1.84 (d.3H), 4.49 (q, 2H), 6.43 (q,1H). 7.58 (t, 1H), 8.03 (t, 1H), 8.08 (s, 1H0, 8.23 (d, 1H), 8.67 (t,1H), 8.73 (s, 1H), 8.39 (d, 2H), 8.88 (d, 2H), 9.06 (s, 2H). 145 457 459(CD₃OD) 1.4 (t, 3H), 3.48 (d, 4H), 3.99 (s, 4H), 4.41 (s, 2H), 7.7 (d,1H), 8.07 (s, 1H) 8.05 (m, 3H), 8.73 (s, 1H), 8.9 (s, 1H), 9.12 (s, 1H).146 — 502.21 (CD₃OD) 8.89 (s, 1H), 8.49 (d, 1H), 8.45 (s, 1H), 8.22 (d,1H), 8.11 (d, 1H), 8.06 (s, 1H), 7.47 (br d, 1H), 7.36 (br s, 1H), 3.91(s, 3H), 3.68-3.89 (br m, 8H), 3.38 (q, 2H), 1.25 (t, 3H) ppm 147 —487.2 (CD₃OD) 8.99 (s, 1H), 8.54 (d, 1H), 8.46 (s, 1H), 8.27 (d, 1H),8.01 (s, 1H), 7.85 (br s, 1H), 6.97 (br s, 1H), 6.91 (br s, 1H), 4.47(q, 2H), 3.66-3.69 (m, 5H), 3.59-3.62 (m, 2H), 2.01-2.06 (m, 2H),1.96-2.00 (m, 2H), 1.43 (t, 3H) ppm 148 375 377 (CD₃OD): 9.02 (t, 2H),8.98 (s, 2H), 8.82 (d, 1H), 8.05 (d, 1H), 7.54 (t, 1H), 4.48 (q, 2H),1.44 (t, 3H) 149 — 486.22 (CD₃OD) 8.98 (s, 1H), 8.44 (m, 1H), 8.38 (brs, 1H), 8.19 (br d, 1H), 8.02 (br s, 1H), 7.98 (br s, 1H), 7.15 (br s,1H), 7.13 (br s, 1H), 3.79 (br s, 3H), 3.67 (m, 2H), 3.61 (m, 2H), 3.37(q, 2H), 2.05 (m, 2H), 2.00 (m, 2H), 1.25 (t, 3H) p 150 494.3 496.2(CD₃OD) 9.0 (d, 2H), 8.8 (s, 1H), 8.6 (d, 1H), 8.2 (t, 1H), 7.95 (s,1H), 7.8 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 6.9 (s, 1H), 6.6 (s, 1H),6.1 (m, 1H), 4.4 (q, 2H), 2.7 (s, 3H), 2.05 (d, 3H), 1.4 (t, 3H) 151493.4 495.2 (CD₃OD) 8.95 (d, 2H), 8.6 (s, 1H), 8.5 (d, 1H), 8.1 (t, 1H),7.8 (s, 1H), 7.7 (d, 1H), 7.5 (t, 1H), 7.4 (t, 1H), 6.8 (s, 1H), 6.6 (s,1H), 6.0 (m, 1H), 3.35 (q, 2H), 2.6 (s, 3H), 2.0 (d, 3H), 1.2 (t, 3H)152 — 462.21 (CD₃OD) 8.90 (d, 1H), 8.81 (d, 1H), 8.49 (m, 1H), 8.39 (d,1H), 8.04 (d, 1H), 7.85 (m, 1H), 7.02 (br s, 1H), 6.90 (d, 1H), 4.82 (m,1H, underneath water peak), 4.42 (q, 2H), 4.29 (m, 1H), 3.72 (m, 1H),3.35 (s, 3H), 2.65 & 2.90 (s, 3H), 1 153 504.3 506.3 12.14 (s, 1H);11.11 (s, 1H); 9.59 (s, 1H); 9.08 (d, 2H); 8.38 (s, 1H); 8.33 (d, 1H);8.22 (s, 1H); 7.95 (d, 1H); 7.56 (dd, 1H); 4.32 (q, 2H); 4.12 (br. s,4H); 3.62 (br. s, 4H); 2.46 (br. s, 2H); 1.31 (dd, 2H); 1.22 (t, 3H).154 474.3 476.3 10.31 (s, 1H); 9.09 (d, 2H); 8.79 (s, 1H); 8.44 (s, 1H);8.42 (s, 1H); 8.00 (s, 1H); 7.68 (t, 2H); 7.7-6.6 (br. s, 3H); 4.32 (q,2H); 3.55 (m, 4H); 3.12 (m, 4H); 2.34 (s, 6H); 1.32 (t, 3H). 155 479.3481.2 1.33 (t, 3H) 2.36 (s, 3H) 4.35 (q, 2H) 5.60 (s, 2H) 6.84 (s, 1H)6.88 (s, 1H) 7.68 (t, 1H)7.81 (d, 2H) 7.99 (s, 1H) 8.26 (t, 1H) 8.35 (s,1H)8.78 (d, 1H) 8.89 (d, 3H) 11.75 (br s, 2H) 156 — 461.22 (CD₃OD) 8.83(m, 1H), 8.44 (d, 1H), 8.25 (d, 1H), 8.12 (m, 1H), 7.88 (d, 1H), 7.54(m, 1H), 6.70 (s, 1H), 6.68 (s, 1H), 4.68 (m, 1H), 4.32 (m, 1H), 3.70(m, 1H), 3.38 (q, 2H), 3.35 (s, 3H), 2.56 (s, 3H), 1.60 (d, 3H), 1.24(t, 3H) ppm 157 486.3 488.3 (CD₃OD) 1.37 (t, 3H) 1.57 (m, 4H) 2.27 (m,1H) 2.82 (s, 3H) 3.41 (t, 2H) 3.96 (d, 2H)4.29 (d, 2H) 4.43 (q, 2H) 7.27(s, 1H) 7.50 (s, 1H) 7.90 (t, 1H) 8.17 (s, 1H) 8.55 (s, 1H) 8.659 (t,1H) 8.95 (d, 1H) 9.09 (d, 1H) 158 474.3 476.3 (CD₃OD) 1.08 (d, 6H) 1.42(t3H) 2.76 (s, 3H) 3.57 (m, 1H) 2.82 (t, 2H)4.42 (m, 4H) 6.98 (s, 1H)7.05 (s, 1H) 7.86 (t, 1H) 8.09 (s, 1H) 8.41 (s, 1H)8.51 (t, 1H) 8.82 (d,1H) 8.91 (d, 1H) 159 458 460 (CD₃OD) 1.43 (t, 3H), 3.48 (bs, 24H), 3.99(bs, 4H), 4.48 (1, 2H), 4.63 (s, 2H), 7.55 (t, 1H), 7.71 (d, 1H), 8.1(s, 1H), 8.33 (d, 1H), 8.9 (1H), 9.03 (d, 2H), 9.13 (s.1H). 160 457 459(CD₃OD) 1.35 (t, 3H), 3.3-3.5 (m, 6H), 3.99 (bs, 4H), 4.62 (s, 2H), 7.52(t, 1H), 7.7 (d, 1H), 8.08 (s, 1H), 8.32 (d, 1H), 8.88 (s, 1H), 9.05 (d,2H)9.1 (s, 1H). 161 446.28 448.2 1.2 (t, 3H), 3.2 (m, 2H), 3.3 (br s,4H), 3.9 (br s, 4H), 4.7 (s, 2H), 7.7 (s, 1H), 7.8 (br s, 1H), 7.95 (m,1H), 8.1 (s, 1H), 8.25 (s, 1H), 8.7 (m, 1H), 8.8 (m, 1H), 9.2 (s, 1H),10.6 (br s, 1H) 162 550.3 552.3 12.32 (s, 1H); 11.18 (s, 1H); 9.08 (d,2H); 8.62 (s, 1H); 8.39 (s, 1H); 8.37 (s, 1H); 7.98 (s, 1H); 7.62 (m,2H); 7.58 (dd, 1H); 7.48 (m, 3H); 6.4-5.9 (br. s, 3H); 4.38 (s, 2H);4.33 (q, 2H); 3.42 (m, 4H); 3.15 (m, 4H); 1.35 (t, 3H). 163 501.3 503.3(CD₃OD) 9.1 (d, 1H), 8.8 (t, 1H), 8.5 (d, 1H), 8.4 (s, 1H), 8.3 (s, 1H),8.2 (t, 1H), 7.7 (s, 1H), 7.5 (s, 1H), 4.8 (t, 2H), 4.4 (q, 2H), 4.1 (d,2H), 3.9 (t, 2H), 3.75 (d, 2H), 3.7 (t, 2H), 3.4 (m, 2H), 3.3 (s, 2H),2.85 (s, 3H), 2.0 (s, 5H), 1.4 (t, 3H) 164 500.4 502.3 (CD₃OD) 8.75 (d,1H), 8.3 (d, 1H), 8.2 (s, 1H), 8.0-8.05 (t, 1H), 7.8 (s, 1H), 7.5 (t,1H), 6.8 (s, 1H), 6.7 (s, 1H), 4.5-4.6 (t, 2H), 4.0 (brd s, 4H), 3.5-3.6(t, 4H), 3.4 (q, 2H), 3.3 (t, 2H), 2.6 (s, 3H), 1.2-1.3 (t, 3H) 165 474476 (CD₃OD) 9.04 (d, 1H), 8.71 (d, 1H), 8.34 (d, 1H), 8.23 (dd, 1H),7.94 (d, 1H), 7.84 (m, 1H), 7.65 (d, 1H), 7.57 (m, 1H), 4.56 (s, 2H),3.98 (t, 4H), 3.45 (t, 4H), 3.37 (q, 2H), 1.24 (t, 3H) 166 475 477(CD₃OD): 9.07 (d, 1H), 8.72 (d, 1H), 8.49 (d, 1H), 8.28 (dd, 1H), 8.04(d, 1H), 7.92 (m, 1H), 7.69 (d, 1H), 7.63 (m, 1H), 4.63 (s, 2H), 4.47(q, 2H), 3.99 (m, 4H), 3.44 (m, 4H), 1.43 (t, 3H) 167 522.3 524.4(CD₃OD) 8.94 (d, 2H), 8.65 (s, 1H), 7.85 (s, 1H), 7.44 (dd, 1H), 7.27(dd, 1H), 6.84 (d, 2H), 6.80 (s, 1H), 6.70 (s, 1H), 6.64 (s, 1H), 3.77(s, 3H), 3.36 (q, 2H), 2.39 (br s, 3H), 1.96 (d, 3H), 1.24 (t, 3H) 168 —474.3 (CD₃OD) 1.45 (t, 3H) 1.80 (d, 3H) 2.69 (m, 2H) 3.50 (m, 2H) 3.97(m, 4H) 4.49 (q, 2H) 4.72 (m, 1H)7.55 (t, 1H) 7.71 (d, 1H) 1.15 (s, 1H)8.33 (d, 1H) 8.91 (s, 1H) 9.08 (d, 2H) 9.17 (s, 1H) 169 445.44 447.241.3 (t, 3H), 2.9 (br s, 6H), 3.6 (brs, 2H), 4.3 (q, 2H), 4.6 (m, 2H),7.1 (m, 1H), 7.6 (m, 1H), 7.9 (s, 1H), 8.2 (m, 1H), 8.25 (s, 1H), 8.3(m, 1H), 8.6 (d, 1H), 8.7 (d, 1H), 9.1 (s, 1H), 9.7 (br, s, !H) 170444.43 446.22 1.2 (t, 3H), 2.9 (br s, 6H), 3.25 (m, 2H), 3.6 (br s, 2H),4.6 (m, 2H), 7.1 (m, 1H), 7.4 (br s, 1H), 7.6 (m, 1H), 7.9 (s, 1H), 8.1(br s, 1H), 8.2 (s, 1H), 8.3 (m, 1H), 8.6 (d, 1H), 8.7 (d, 1H), 9.1 (s,1H), 9.8 (br s, 1H), 10.5 (br s, 1H) 171 460.2 462.2 (CD₃OD) 8.95 (d,1H), 8.86 (d, 1H), 8.57 (dt, 1H), 8.46 (d, 1H), 8.17 (d, 1H), 7.93 (t,1H), 7.62 (br s 1H), 7.33 (d, 1H), 5.14 (m, 1H), 4.42 (q, 2H), 4.26 (m,1H), 3.75 (dd, 1H), 3.36 (s, 3H), 2.81 (s, 3H), 1.42 (d, 3H), 1.30 (t,3H) ppm 172 485 487 (CD₃OD) 1.45-1.12 (m, 3H), 1.9 (m, 1H), 2.1 (m, 2H),2.32 (m, 1H), 3.5-3.3 (m, 5H), 3.7 (m, 4H), 3.99 (bs, 1H), 4.4 (q, 2H),4.57 (bd, 1H), 7.58 (d, 1H), 7.8 (t, 1H), 8.03 (s, 1H0, 8.32 (d, 1H),8.42 (m, 2H), 8.75 (d, 1H), 8.88 (s, 1H) 9.1 (s, 1H). 173 484 486(CD₃OD) 1.15 (t, 3H), 1.4 (t, 3H), 3.02 (s, 2H), 3.6 (m, 2H), 3.68 (m,2H), 3.95 (s, 2H), 4.4 (m, 2H), 4.61 (s, 2H), 7.8 (m, 2H), 8.08 (s, 1H),8.48 (m, 3H), 8.78 (d, 1H), 8.9 (d, 1H), 9.17 (s, 1H). 174 503.2 505.2(CDCl₃) 8.94 (d, 1H), 8.87 (d, 1H), 8.15 (d, 1H), 8.11 (d, 2H), 7.95(ddd, 1H), 7.90 (s, 1H), 7.70 (d, 1H), 7.42 (dd, 1H), 4.76 (s, 2H), 4.46(q, 2H), 3.82 (t, 4H), 3.64 (t, 4H), 3.40 (s, 6H), 1.45 (t, 3H) 175593.4 595.3 10.85 (s, 1H); 8.84 (s, 1H); 8.72 (s, 1H); 8.58 (d, 1H);8.52 (s, 1H); 8.30 (d, 1H); 8.08 (s, 1H); 7.92 (d, aH); 7.44 (d, 2H);7.34 (dd, 2H); 7.24 (t, 1H); 6.05-4.9 (br. s); 5.21 (dq, 1H); 4.78 (d,2H); 4.31 (q, 2H); 3.58 (d, 2H); 3.52 ( 176 543.5 545.3 11.76 (s, 1H);9.59 (s, 1H); 8.89 (d, 1H); 8.78 (s, 1H); 8.65 (s, 1H); 8.40 (s, 1H);8.05 (d, 1H); 7.9-6.2 (br. s, 2H); 4.87 (d, 2H); 4.32 (q, 2H); 3.96 (dd,2H); 3.68 (dd, 2H); 3.58 (m, 4H); 3.20 (m, 2H); 2.94 (d, 3H); 1.98 (m,2H); 1.88 177 542.5 544.3 11.12 (s, 1H); 10.84 (s, 1H); 9.08 (s, 1H);8.87 (d, 1H); 8.66 (s, 1H); 8.41 (s, 1H); 8.01 (s, 1H); 7.96 (d, 1H);7.58 (s, 1H); 6.3-4.6 (br. s, 6H); 4.82 (d, 2H); 3.96 (dd, 2H); 3.58 (m,6H); 3.26 (m, 2H); 3.15 (m, 2H); 2.84 (d, 3H); 1.96 ( 178 470.4 472.39.05 (d, 2H); 8.54 (s, 1H); 7.89 (s, 1H); 8.01 (s, 1H); 7.78 (d, 1H);7.55 (t, 1H); 7.05 (d, 1H); 5.5-4.2 (br. s, 1H); 4.33 (q, 2H); 3.50 (dd,2H); 3.36 (dd, 2H); 3.12 (s, 3H); 2.85 (s, 3H); 1.33 (t, 3H). 179 415.4417.3 (CD₃OD) 9.54 (d, 1H), 9.21 (m, 1H), 9.15 (s, 1H), 8.97 (d, 1H),8.92 (d, 1H), 8.83 (d, 1H), 8.28 (dd, 1H), 8.20 (d, 1H), 7.69 (m, 1H),4.62 (s, 2H), 4.48 (q, 2H), 3.00 (s, 6H), 1.44 (t, 3H) ppm 180 414.4416.3 (CD₃OD) 9.54 (d, 1H), 9.22 (m, 1H), 9.05 (s, 1H), 8.97 (d, 1H),8.93 (d, 1H), 8.79 (d, 1H), 8.28 (dd, 1H), 8.17 (d, 1H), 7.62 (m, 1H),4.59 (s, 2H), 3.39 (q, 2H), 2.99 (s, 6H), 1.25 (t, 3H) ppm 181 513 515(CD₃OD): 9.14 (d, 1H), 9.06 (d, 1H), 8.85 (t, 1H), 8.67 (t, 1H), 8.46(d, 1H), 8.37 (d, 1H) 8.11 (m, 1H), 7.97 (d, 1H), 7.55 (m, 1H), 4.07(brs, 2H), 3.88 (t, 4H), 3.71 (brs, 2H), 3.48 (t, 4H), 3.36 (q, 2H),1.24 (t, 3H) 182 477.4 479.37 0.9 (d, 6H), 1.3 (t, 3H), 2.1 (m, 1H), 2.9(s, 6H), 3.75 (d, 2H), 4.3 (q, 2H), 4.6 (s, 2H), 6.6 (dt, 1H), 6.7 (d,1H), 7.7 (s, 1H), 7.8 (d, 1H), 7.95 (s, 1H), 8.010.2 (br s, 1H) (s, 1H),183 476.42 478.41 0.9 (d, 6H), 1.1 (t, 3H), 2.1 (m, 1H), 2.9 (s, 6H),3.2 (m, 2H), 3.8 (d, 2H), 4.6 (s, 2H), 6.6 (dt, 1H), 6.7 (d, 1H), 7.3(br s, 1H), 7.7 (s, 1H), 7.8 (d, 1H), 7.95 (s, 1H), 8.0 (s, 1H), 10.2(br s, 1H) 184 514 516 — 185 470.4 472.2 (CD₃OD) 1.25 (t, 3H) 1.78 (d,3H) 3.30 (m, 2H) 3.35 (q, 2H) 3.50 (m, 2H) 3.93 (m, 4H)4.73 (q, 1H) 7.72(t, 1H) 7.45 (d, 1H) 8.01 (s, 1H) 8.27 (t, 1H) 8.35 (m, 2H) 8.52 (d, 1H)8.91 (d, 1H) 9.18 (s, 1H) 186 498.4 500.3 (CD₃OD) 1.16 (m, 3H) 1.26 (m,6H) 1.80 (d, 3H) 2.82 (t, 2H) 3.20 (d, 1H) 3.35 (q, 2H)3.72 (d, 1H) 3.91(m, 1H) 4.04 (m, 1H) 4.68 (q, 1H) 7.65 (t, 1H) 7.71 (d, 1H) 8.01 (s,1H)8.22 (t, 1H) 8.35 (m, 2H) 8.49 (d, 1H) 8.89 (d, 1H) 9.18 (s, 1H) 187499.5 501.3 (CD₃OD) 1.16 (m, 3H) 1.29 (d, 3H) 1.41 (t, 3H) 1.79 (d, 3H)2.82 (t, 2H) 3.20 (d, 1H) 3.74 (d, 1H) 3.92 (m, 1H) 4.04 (m, 1H) 4.43(q, 2H) 4.69 (q, 1H) 7.70 (d, 1H)7.87 (t, 1H) 8.11 (s, 1H) 8.35 (d, 1H)8.46 (m, 2H) 8.75 (d, 1H) 8.92 (d, 1H) 9.34 (s, 1H) 188 486 488 (CD₃OD):8.91 (m, 1H), 8.65 (m, 1H), 8.47 (m, 1H), 8.31 (m, 2H), 8.29 (m, 1H),7.96 (m, 1H) 7.73 (m, 1H), 7.19 (m, 1H), 4.08 (m, 2H), 3.90 (m, 2H),3.72 (m, 4H), 3.66 (m, 4H), 3.37 (m, 2H), 1.24 (t, 3H) 189 487 489(CD₃OD): 8.89 (d, 1H), 8.69 (d, 1H), 8.61 (d, 1H), 8.41 (t, 1H), 8.32(d, 1H), 8.20 (dd, 1H) 7.95 (d, 1H), 7.78 (t, 1H), 7.10 (d, 1H), 4.42(q, 2H), 4.09 (m, 2H), 3.86 (m, 2H), 3.70 (m, 4H), 3.33 (m, 4H), 1.24(t, 3H) 190 388.38 390.19 1.2 (t, 3H), 3.3 (m, 2H), 3.5 (s, 3H), 6.6(dd, 1H), 6.7 (d, 1H), 7.6 (t, 1H), 7.8 (d, 1H), 7.95 (br s, 1H), 8.0(s, 1H), 8.6 (s, 1H), 9.05 (d, 2H) 191 359.3 361.2 — 192 446.4 448.3 —193 474.2 476.4 (CD₃OD) 9.14 (s, 1H), 9.08 (d, 2H), 8.91 (s, 1H), 8.39(d, 1H), 8.14 (s, 1H), 7.78 (s, 1H), 7.55 (dd, 1H), 4.72 (s, 2H), 4.48(q, 2H), 3.81 (t, 2H), 3.56 (t, 2H), 3.46 (q, 2H), 3.41 (s, 3H), 1.44(t, 3H), 1.43 (t, 3H) 194 486.1 488.1 (CDCl₃) 12.31 (br s, 1H), 8.95 (s,1H), 8.93 (d, 2H), 8.58 (s, 1H), 8.05 (s, 1H), 8.01 (d, 1H), 7.50 (d,1H), 7.24 (dd, 1H), 4.46 (q, 2H), 3.78 (m, 2H), 3.72 (s, 2H), 2.78 (d,2H), 1.91 (dd, 2H), 1.41 (t, 3H), 1.17 (d, 6H) 195 — — 11.5 (br s, 1H),9.19 (br s, 1H), 8.97 (s, 1H), 8.88 (d, 1H), 8.45 (m, 1H), 8.40 (s, 1H),7.98 (d, 1H), 7.77 (d, 1H), 7.60 (d, 1H), 4.57 (s, 2H), 4.47 (br d, 2H),4.32 (q, 2H), 3.90 (br m, 4H), 3.32 (br s, 4H), 2.80 (d, 6H), 1.34 197460.2 462.2 (CD₃OD &CDCl₃): 8.98 (d, 2H), 8.85 (d, 1H), 8.60 (d, 1H),8.16 (dd, 1H), 7.86 (d, 1H), 7.67 (d, 1H), 7.40 (dd, 1H), 4.37 (q, 2H),3.81 (s, 2H), 3.60 (t, 2H), 3.37 (s, 3H), 2.74 (t, 2H), 2.38 (s, 3H),1.41 (t, 3H) 198 459.3 461.2 (CD₃OD): 8.95 (d, 2H), 8.83 (s, 1H), 8.54(s, 1H), 8.15 (d, 1H), 7.82 (s, 1H), 7.65 (d, 1H), 7.39 (dd, 1H), 3.79(s, 2H), 3.59 (t, 2H), 3.36 (q, 2H), 3.35 (s, 3H), 2.72 (t, 2H), 2.36(s, 3H), 1.24 (t, 3H) 199 488 490 — 200 487 489 — 201 488 490 — 202 487489 — 203 489 491 9.06 (m, 4H), 8.50 (d, 1H), 7.98 (d, 1H), 7.54 (t,1H), 4.79 (t, 2H), 4.31 (q, 2H), 4.01 (m, 2H), 3.79 (m, 2H), 3.67 (m,2H), 3.56 (m, 2H), 3.25 (m, 2H) 1.33 (t, 3H) 204 488 490 (CD₃OD): 9.02(m, 4H), 8.75 (s, 1H), 7.97 (d, 1H), 7.52 (m, 1H), 4.88 (m, 2H),3.75-3.73 (m, 10H), 3.35 (m, 2H), 1.25 (t, 3H) 205 400.1 402.1 1.31 (t,3H) 2.70 (s, 3H) 4.32 (q, 2H) 7.55 (t, 1H) 8.00 (s, 1H) 8.09 (d, 1H)8.14(t, 1H) 8.39 (s, 1H) 8.44 (d, 1H) 8.70 (d, 1H) 8.81 (d, 1H) 9.19 (s, 1H)206 458.1 460 (CD₃OD) 9.41 (d, 2H), 8.92 (m, 1H), 8.80 (d, 1H), 8.48 (m,2H), 8.10 (br s, 1H), 7.84 (m, 1H), 4.76 (s, 2H with water peak), 4.42(q, 2H), 4.11 (br m, 2H), 3.95 (nr m, 2H), 3.71 (br m, 2H), 3.45 (br m,2H), 1.42 (t, 3H) ppm. 207 457.2 459.1 (CD₃OD) 9.33 (s, 2H), 8.89 (d,1H), 8.53 (d, 1H), 8.44 (d, 1H), 8.20 (m, 1H), 8.04 (d, 1H), 7.63 (m,1H), 4.76 (s, 2H, with water peak), 4.12 (br m, 2H), 3.94 (br m, 2H),3.71 (br m, 2H), 3.44 (br m, 2H), 3.39 (q, 2H), 1.25 (t, 3H) ppm 208 391393 — 209 441.1 443 (CD₃OD) 1.43 (t, 3H) 4.50 (s, 2H) 4.89 (s, 2H) 7.55(t, 1H) 8.10 (d, 1H)8.20 (s, 1H) 8.87 (d, 1H) 9.01 (s, 1H) 9.10 (d, 2H)9.30 (s, 1H) 210 472.4 474.2 (CD₃OD) 9.25 (s, 1H), 9.02 (d, 2H), 8.87(d, 1H), 8.65 (d, 1H), 8.18 (s, 1H), 8.08 (d, 1H), 7.54 (dd, 1H), 4.88(s, 2H), 4.49 (q, 2H), 4.27 (br s, 1H), 3.68 (m, 4H), 3.40 (s, 3H), 2.32(m, 2H), 1.45 (t, 3H) 211 471.2 473.1 (CD₃OD) 9.16 (s, 1H), 8.98 (d,2H), 8.76 (d, 1H), 8.48 (d, 1H), 8.05 (s, 1H), 7.91 (d, 1H), 7.50 (dd,1H), 4.81 (s, 2H), 4.27 (br s, 1H), 3.69 (m, 4H), 3.40 (s, 3H), 3.38 (q,2H), 2.32 (m, 2H), 1.26 (t, 3H) 212 485.2 487.3 (CD₃OD) 9.16 (s, 1H),9.03 (d, 2H), 8.87 (s, 1H), 8.50 (d, 1H), 8.14 (s, 1H), 7.92 (d, 1H),7.54 (dd, 1H), 4.75 (s, 2H), 4.49 (q, 2H), 4.06 (s, 2H), 3.74 (br s,4H), 3.06 (s, 3H), 1.45 (t, 3H) 213 484.2 486.2 (CD₃OD) 9.16 (s, 1H),9.01 (d, 2H), 8.78 (s, 1H), 8.52 (d, 1H), 8.07 (s, 1H), 7.96 (d, 1H),7.52 (dd, 1H), 4.77 (s, 2H), 4.07 (s, 2H), 3.75 (br s, 4H), 3.38 (q,2H), 3.06 (s, 3H), 1.26 (t, 3H) 214 350.1 12.28 (br. s, 1H); 11.77 (br.s, 1H); 9.73 (s, 1H); 9.08 (d, 2H); 8.49 (d, 1H); 8.37 (m, 1H); 8.08 (d,1H); 7.94 (m, 1H); 7.59 (t, 1H); 4.32 (q, 2H); 2.30 (s, 3H); 1.32 (t,3H). 215 502.4 504.1 (CD₃OD) 9.17 (s, 1H), 9.02 (d, 2H), 8.85 (s, 1H),8.48 (d, 1H), 8.15 (s, 1H), 7.90 (d, 1H), 7.53 (dd, 1H), 4.81 (d, 1H),4.77 (d, 1H), 4.48 (q, 2H), 4.18 (br s, 2H), 3.75 (m, 4H), 3.47 (s, 6H),1.45 (t, 3H) 216 347.2 349.1 12.28 (br. s, 1H); 10.22 (br. s, 1H); 9.53(s, 1H); 9.08 (d, 2H); 8.41 (d, 1H); 8.29 (m, 1H); 7.98 (d, 1H); 7.83(m, 1H); 7.57 (t, 1H); 7.22 (m, 1H); 3.26 (dq, 2H); 2.31 (s, 3H); 1.15(t, 3H). 217 501.4 503.1 (CD₃OD) 9.15 (s, 1H), 9.03 (d, 2H), 8.85 (s,1H), 8.43 (d, 1H), 8.10 (s, 1H), 7.83 (d, 1H), 7.53 (dd, 1H), 4.78 (d,1H), 4.74 (d, 1H), 4.18 (br s, 2H), 3.74 (m, 4H), 3.47 (s, 6H), 3.38 (q,2H), 1.26 (t, 3H) 218 456 458 (CD₃OD) 1.24 (t, 3H), 3.38 (m, 2H), 3.57(bs, 4H), 3.99 (bs, 4H), 4.63 (s, 2H), 7.68 (m, 1H), 7.73 (m, 1H), 8.02(s, 1H), 8.24 (t, 1H), 8.48 (m, 1H), 8.49 (d, 1H), 8.9 (d, 1H), 9.13 (s,1H). 219 — — 12.25 (s, 1H); 11.75 (s, 1H); 9.61 (d, 1H); 9.07 (d, 2H);8.45 (s, 1H); 8.11 (s, 1H); 8.02 (d, 1H); 7.59 (t, 1H); 4.31 (q, 2H);2.38 (s, 3H); 2.29 (s, 3H); 1.32 (t, 3H). 220 502.3 504.2 (CD₃OD) 9.10(d, 1H), 9.05 (d, 2H), 8.91 (d, 1H), 8.32 (dd, 1H), 8.11 (d, 1H), 7.69(d, 1H), 7.55 (dd, 1H), 4.73 (d, 1H), 4.69 (d, 1H), 4.49 (q, 2H), 4.17(br s, 2H), 3.70 (m, 4H), 3.46 (s, 6H), 1.44 (t, 3H) 221 501.3 503.2(CD₃OD) 9.09 (s, 1H), 9.05 (d, 2H), 8.86 (s, 1H), 8.29 (d, 1H), 8.09 (s,1H), 7.67 (d, 1H), 7.54 (dd, 1H), 4.72 (d, 1H), 4.67 (d, 1H), 4.17 (brs, 2H), 3.71 (m, 4H), 3.47 (s, 6H), 3.39 (q, 2H), 1.26 (t, 3H) 222 — 559(CDCl₃) 12.29 (br s, 1H), 8.94 (s, 1H), 8.94 (d, 2H), 8.60 (s, 1H), 8.04(s, 1H), 8.02 (d, 1H), 7.50 (d, 1H), 7.25 (dd, 1H), 4.46 (q, 2H), 3.75(s, 2H), 3.50 (m, 4H), 2.51 (m, 4H), 1.47 (s, 9H), 1.41 (t, 3H) 223513.2 515.14 1.1 (d, 6H), 1.3 (t, 3H), 3.5 (m, 4H), 3.7 (br s, 2H), 4.3(q, 2H), 4.5 (br s, 2H), 4.65 (m, 1H), 7.5 (t, 1H), 7.7 (d, 1H), 8.0 (d,1H), 8.3 (dd, 1H), 8.5 (d, 1H), 9.0 (d, 2H), 9.05 (d, 1H) 224 457.207459.207 (CD₃OD) 9.54 (s, 1H), 9.28 (s, 1H), 9.22 (d, 1H), 8.97 (d, 1H),8.93 (d, 1H), 8.85 (br s, 1H), 8.27 (t, 1H), 8.20 (br s, 1H), 7.71 (d,1H), 4.63 (s, 2H), 4.48 (q, 2H), 4.05 (br s, 4H), 3.44 (br m, 4H), 1.44(t, 3H) ppm 225 472.2 474.49 (CD₃OD) 9.0 (d, 1H), 8.95 (m, 1H), 8.6 (s,1H), 8.5 (s, 1H), 8.4 (s, 1H), 8.3 (s, 1H), 7.9 (s, 1H), 7.55 (m, 1H),4.5 (s, 2H), 3.9 (s, 2H), 3.4 (q, 2H), 3.0 (s, 6H), 1.3 (t, 3H). 226562.3 564.2 (CD₃OD) 9.0 (d, 1H), 8.9 (m, 1H), 8.6 (s, 1H), 8.5 (s, 1H),8.3 (s, 1H), 8.25 (s, 1H), 7.9 (s, 1H), 7.55 (m, 1H), 7.3-7.4 (m, 5H),5.2 (s, 2H), 4.5 (s, 2H), 4.0 (s, 2H), 3.4 (q, 2H), 3.0 (s, 6H), 1.3 (t,3H) 227 389 391 — 228 457.3 459.1 — 229 456.3 458.1 — 230 433.3 435.1 —231 487 489 (CD₃OD) 9.30 (s, 2H), 9.04 (d, 2H), 8.89 (d, 1H), 8.11 (d,1H), 7.54 (t, 1H), 4.46 (q, 2H), 4.02 (m, 2H), 3.59 (m, 2H), 2.89 (m,2H), 1.44 (t, 2H), 1.13 (t, 3H) ppm. 232 456.3 458.3 (CD₃OD) 9.22 (s,1H), 9.05 (d, 2H), 8.92 (s, 1H), 8.78 (d, 1H), 8.17 (s, 1H), 8.08 (d,1H), 7.54 (dd, 1H), 4.42 (s, 2H), 3.,52 (m, 4H), 3.39 (q, 4H), 3.28 (m,4H), 1.26 (t, 3H) 233 — 459.1 (CD₃OD) 9.22 (s, 1H), 9.06 (d, 2H), 8.96(s, 1H), 8.77 (d, 1H), 8.22 (s, 1H), 8.07 (d, 1H), 7.56 (dd, 1H), 4.49(q, 2H), 4.42 (s, 2H), 3.,52 (m, 4H), 3.29 (m, 4H), 1.45 (t, 3H) 234 —537 (CD₃OD) 9.22 (s, 1H), 9.04 (d, 2H), 8.90 (s, 1H), 8.54 (d, 1H), 8.16(s, 1H), 7.99 (d, 1H), 7.54 (dd, 1H), 4.78 (s, 2H), 4.49 (q, 2H), 3.69&3.63 (m, 8H), 3.00 (s, 3H), 1.45 (t, 3H) 235 534.2 536.1 (CD₃OD) 9.20(s, 1H), 9.02 (d, 2H), 8.82 (s, 1H), 8.52 (d, 1H), 8.09 (s, 1H), 7.98(d, 1H), 7.52 (dd, 1H), 4.78 (s, 2H), 3.69 &3.62 (m, 8H), 3.39 (q, 2H),3.00 (s, 3H), 1.25 (t, 3H) 236 496.4 498.3 (CD₃OD) 9.28 (s, 1H), 9.06(br s, 2H), 8.96 (s, 1H), 8.85 (br s, 1H), 8.24 (s, 1H), 8.15 (br s,1H), 7.56 (br s, 1H), 4.49 (q, 2H), 4.42 (s, 2H), 3.73 (br s, 4H), 3.35(br s, 4H), 3.01 (br s, 1H), 1.45 (t, 3H), 1.20 (br s, 2H), 1.00 (br s2H) 237 496.4 498.3 (CDCl₃) 11.82 (br s, 1H), 8.88 (s, 1H), 8.71 (br s,2H), 8.48 (s, 1H), 7.89 (d, 1H), 7.79 (s, 1H), 7.42 (d, 1H), 7.05 (br s,1H), 3.71 (s, 2H), 3.46 (q, 2H), 2.70 & 2.55 (m, 8H), 1.28 (t, 3H),0.45-0.41 (m, 4H) 238 447.2 449 12.35 (s, 1H); 9.07 (d, 2H); 8.82 (s,1H); 8.41 (d, 1H); 8.13 (s, 1H); 7.95 (d, 1H); 7.57 (t, 1H); 6.7-5.2(br. s, 4H); 4.38 (s, 2H); 4.32 (q, 2H); 3.92 (br. d, 4H); 3.32 (br. d,4H); 1.33 (t, 3H). 239 490.1 492.2 (CD₃OD) 9.21 (s, 1H), 9.05 (d, 2H),8.92 (s, 1H), 8.54 (d, 1H), 8.17 (s, 1H), 7.97 (d, 1H), 7.55 (dd, 1H),4.78 (s, 2H), 4.49 (q, 2H), 4.01 (br dd, 2H), 3.74 (br d, 2H), 3.43 (brdd, 2H), 3.27 (br d, 2H), 1.45 (t, 3H) 240 471.3 473 (CD₃OD) 9.28 (s,1H), 9.05 (br s, 2H), 8.96 (s, 1H), 8.89 (s, 1H), 8.25 (s, 1H), 8.17 (s,1H), 7.55 (br s, 1H), 4.49 (q, 2H), 4.39 (s, 2H), 3.64-3.13 (m, 8H),3.00 (s, 3H), 1.45 (t, 3H) 241 — 531.01 1.3 (t, 3H), 1.55 (d, 3H), 3.3(br s, 4H), 3.9 (br s, 4H), 4.0 (q, 1H), 4.35 (q, 2H), 4.6 (s, 2H), 7.6(dd, 1H), 7.8 (d, 1H), 8.0 (s, 1H), 8.4 (d, 1H), 8.42 (s, 1H), 8.7 (s,1H), 8.8 (d, 1H), 9.15 (s, 1H), 11...2 (br s, 1H) 242 486.2 488.1(CD₃OD) 9.33 (s, 2H), 8.92 (d, 1H), 8.79 (d, 1H), 8.47 (m, 2H), 8.09 (d,1H), 7.84 (m, 1H), 4.42 (q, 2H), 4.05 (m, 2H), 3.67 (m, 2H), 3.39 (m,2H, underneath solvent peak), 3.00 (m, 2H), 1.42 (t, 3H), 1.28 (d, 6H)ppm 243 488.2 490.05 1.3 (t, 3H), 3.2 (m, 2H), 3.5 (m, 2H), 3.7 (m, 2H),3.9 (m, 2H), 4.0 (m, 2H), 4.3 (q, 2H), 4.8 (m, 2H), 7.6 (7, 1H), 8.1 (d,1H), 8.2 (br s, 1H), 8.6 (d, 1H), 8.65 (d, 1H), 8.8 (d, 1H), 9.05 (d,2H), 11.6 (br s, 1H), 12.7 (br s, 1H) 244 457.21 459.09 1.35 (t, 3H),2.8 (br s, 3H), 3.2 (m, 2H), 3.4 (m, 2H), 3.55 (m, 2H), 4.3 (m, 2H),4.35 (q, 2H), 7.6 (t, 1H), 8.1 (d, 1H), 8.3 (br s, 1H), 8.55 (d, 1H),8.6 (d, 1H), 8.7 (d, 1H), 9.05 (d, 2H), 11.2 (br s, 1H), 12.4 (br s, 1H)245 529.2 531.1 (CD₃OD) 9.08 (d, 1H), 9.01 (d, 2H), 8.82 (d, 1H), 8.30(d, 1H), 8.04 (d, 1H), 7.68 (d, 1H), 7.51 (dd, 1H), 4.63 (s, 2H), 4.47(q, 2H), 4.22 (s, 2H), 3.91 (br s, 4H), 3.49 (br s, 4H), 3.43 (s, 3H),1.44 (t, 3H) 246 555.3 557.1 (CD₃OD) 9.23 (s, 1H), 9.04 (d, 2H), 8.90(s, 1H), 8.56 (d, 1H), 8.17 (s, 1H), 8.00 (d, 1H), 7.55 (dd, 1H), 4.77(s, 2H), 4.49 (q, 2H), 4.12-3.84 (m, 6H), 3.57 (br s, 4H), 3.48 (br s,1H), 2.18 (m, 2H), 1.97 (m, 2H), 1.45 (t, 3H) 247 485.1 487 (CD₃OD) 9.34(s, 2H), 8.93 (d, 1H), 8.80 (d, 1H), 8.48 (m, 2H), 8.10 (d, 1H), 7.85(t, 1H), 4.88 (s, 2H), 4.44 (q, 2H), 4.21 (s, 2H), 3.86 (m, 2H), 3.79(m, 2H), 3.09 (s, 3H), 1.42 (t, 3H) ppm. 248 458.15 460.02 1.23 (t, 3H)3.17 (m, 4H) 3.65 (m, 4H) 4.34 (q, 2H) 4.77 (s, 2H)7.57 (t, 1H) 8.11 (s,1H) 8.61 (s, 1H) 9.06 (d, 2H) 9.39 (s, 2H) 9.87 (br s, 2H) 249 472.3 474(CD₃OD) 9.17 (s, 1H), 9.04 (d, 2H), 8.92 (s, 1H), 8.45 (d, 1H), 8.15 (s,1H), 7.87 (d, 1H), 7.55 (dd, 1H), 4.68 (s, 2H), 4.69 (q, 2H), 4.11 (dd,1H), 4.02-3.95 (m, 2H), 3.57 (m, 2H), 3.03 (dd, 1H), 1.44 (t, 3H), 1.26(d, 3H) 250 499.2 501.3 (CD₃OD) 9.25 (s, 1H), 9.06 (d, 2H), 8.97 (s,1H), 8.84 (d, 1H), 8.23 (s, 1H), 8.12 (d, 1H), 7.56 (dd, 1H), 4.49 (q,2H), 4.37 (s, 2H), 3.65-3.12 (m, 9H), 1.46-1.43 (m, 9H) 251 514.9 517(CD₃OD) 9.27 (s, 1H), 9.05 (d, 2H), 8.95 (s, 1H), 8.86 (d, 1H), 8.25 (s,1H), 8.16 (d, 1H), 7.56 (dd, 1H), 4.49 (q, 2H), 4.46 (s, 2H), 3.81-3.50(m, 12H), 3.44 (s, 3H), 1.45 (t, 3H) 252 527.2 529 (CD₃OD) 9.06 (s, 1H),8.97 (d, 2H), 8.76 (s, 1H), 8.28 (d, 1H), 8.00 (s, 1H), 7.69 (d, 1H),7.49 (dd, 1H), 4.65 (s, 2H), 4.45 (q, 2H), 3.99 (br s, 4H), 3.49 (br s,4H), 2.99 (hept, 1H), 1.44 (t, 3H), 1.14 (d, 6H) 253 502 504 (CD₃OD)9.08 (d, 2H), 8.73 (s, 1H), 8.51 (s, 1H), 8.38 (dd, 1H), 8.07 (d, 1H),7.92 (m, 1H), 7.77 (d, 1H), 7.64 (m, 1H), 4.67 (s, 2H), 4.48 (q, 2H),4.01 (s, 2H), 3.65 (m, 4H), 3.06 (m, 2H), 1.43 (t, 2H), 1.13 (t, 3H)ppm. 254 454.17 456.02 14.52 (s, 1H); 9.22 (s, 2H); 9.05 (d, 2H); 8.56(d, 1H); 8.04 (d, 1H); 7.74 (s, 1H); 7.62 (s, 1H); 7.55 (t, 1H); 6.8-5.6(br. s); 5.79 (s, 2H); 4.33 (q, 2H); 2.62 (s, 3H); 1.33 (t, 3H). 255530.17 532.03 1.1 (d, 6H), 1.35 (t, 3H), 2.3 (s, 6H), 3.5 (m, 2H), 3.6(m, 2H), 3.9 (s, 2H), 4.3 (q, 2H), 4.6 (s, 2H), 4.65 (m, 1H), 7.7 (d,1H), 7.9 (s, 1H), 8.0 (dt, 1H), 8.3 (s, 1H), 8.4 (dd, 1H), 8.8 (d, 1H),8.85 (m, 1H), 9.1 (s, 1H) 256 486.23 488.05 1.3 (d, 6H), 1.35 (t, 3H),3.1 (m, 2H), 3.5 (m, 1H), 3.6 (m, 4H), 4.3 (q, 2H), 4.8 (m, 2H), 7.6 (t,1H), 7.9 (s, 1H), 8.5 (s, 1H), 8.9 (s, 2H), 9.05 (d, 1H), 10.5 (br s,1H) 257 499.2 501.1 (CD₃OD) 9.34 (s, 2H), 8.93 (m, 1H), 8.81 (d, 1H),8.49 (m, 2H), 8.11 (d, 1H), 7.85 (t, 1H), 4.87 (s, 2H), 4.42 (q, 2H),4.11 (br s, 2H), 3.87 (br m, 4H), 3.71 (m, 3H), 1.48 (d, 6H), 1.42 (t,3H) ppm. 258 571.3 573.1 (CDCl₃) 12.75 (br s, 1H), 12.29 (s, 1H), 8.94(d, 2H), 8.92 (s, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 8.04 (d, 1H), 7.59(d, 1H), 7.25 (dd, 1H), 4.46 (q, 2H), 4.23 (br s, 1H), 3.86 (d, 1H),3.80 (d, 1H), 3.65 (d, 1H), 3.19 (ddd, 1H), 2.86 (d, 1H), 2.66 (d, 1H)259 — 473 (CD₃OD) 9.24 (s, 1H), 9.04 (d, 2H), 8.94 (s, 1H), 8.81 (d,1H), 8.22 (s, 1H), 8.11 (d, 1H), 7.55 (dd, 1H), 4.49 (q, 2H), 4.42 (s,2H), 3.77-2.89 (m, 7H), 1.45 (t, 3H), 1.41 (d, 3H) 260 485.3 487.3(CD₃OD) 9.24 (s, 1H), 9.06 (d, 2H), 8.96 (s, 1H), 8.83 (d, 1H), 8.23 (s,1H), 8.11 (d, 1H), 7.56 (dd, 1H), 4.49 (q, 2H), 4.39 (s, 2H), 3.76 (m,2H), 3.40 (d, 2H), 2.80 (d, 2H), 1.45 (t, 3H), 1.40 (d, 6H) 261 485.2487 (CD₃OD) 9.23 (s, 1H), 9.06 (d, 2H), 8.97 (s, 1H), 8.82 (d, 1H), 8.24(s, 1H), 8.13 (d, 1H), 7.56 (dd, 1H), 4.74 (d, 2H), 4.49 (q, 2H), 4.25(d, 1H), 3.80-2.92 (m, 6H), 1.45 (t, 3H), 1.36 (d, 6H) 262 513.2 515(CD₃OD) 9.10 (s, 1H), 9.02 (d, 2H), 8.85 (s, 1H), 8.31 (d, 1H), 8.06 (s,1H), 7.68 (d, 1H), 7.52 (dd, 1H), 4.62 (s, 2H), 4.46 (q, 2H), 3.92-3.16(m, 8H), 2.48 (q, 2H), 1.86 (m, 2H), 1.44 (t, 3H), 1.14 (t, 3H) 263 —557.3 (CD₃OD) 9.11 (s, 1H), 9.03 (d, 2H), 8.85 (s, 1H), 8.32 (d, 1H),8.07 (s, 1H), 7.69 (d, 1H), 7.52 (dd, 1H), 4.63 (s, 2H), 4.47 (q, 2H),3.99-3.79 (m, 8H), 3.50-3.45 (m, 5H), 2.15 (m, 2H), 1.44 (t, 3H) 264 —501.1 (CD₃OD) 9.10 (s, 1H), 9.03 (d, 2H), 8.85 (s, 1H), 8.62 (d, 1H),8.08 (s, 1H), 7.94 (d, 1H), 7.52 (dd, 1H), 4.46 (q, 2H), 4.12 (s, 2H),3.46-3.01 (m, 10H), 1.80 (m, 2H), 1.43 (t, 3H), 1.04 (t, 3H) 265 — 531.1(CD₃OD) 9.21 (s, 1H), 8.96 (d, 2H), 8.82 (s, 1H), 8.59 (d, 1H), 8.12 (s,1H), 8.06 (d, 1H), 7.48 (dd, 1H), 4.75 (s, 2H), 4.42 (q, 2H), 4.12 (q,2H), 3.83 (br s, 4H), 3.47 (br s, 4H), 1.38 (t, 3H), 1.23 (t, 3H) 266543.2 545 (CD₃OD) 9.33 (s, 1H), 8.99 (d, 2H), 8.83 (s, 1H), 8.79 (br s,1H), 8.18 (s, 1H), 7.54 (br s, 1H), 4.93 (m, 1H), 4.89 (s, 2H), 4.49 (q,2H), 3.90 (br s, 4H), 3.57 (br s, 4H), 1.45 (t, 3H), 1.29 (d, 6H) 267516 518 — 268 557.3 559.2 (CD₃OD) 9.08 (s, 1H), 8.969 (d, 2H), 8.78 (s,1H), 8.29 (d, 1H), 8.01 (s, 1H), 7.67 (d, 1H), 7.49 (dd, 1H), 4.62 (s,2H), 4.45 (q, 2H), 3.93 (d, 2H), 3.85 (br s, 4H), 3.46 (br s, 4H), 1.96(m, 1H), 1.43 (t, 3H), 0.98 (d, 6H) 269 553.3 555.1 (CD₃OD) 9.15 (s,1H), 9.05 (d, 2H), 8.91 (s, 1H), 8.39 (d, 1H), 8.14 (s, 1H), 7.79 (d,1H), 7.55 (dd, 1H), 4.71 (q, 2H), 4.68 (s, 2H), 4.49 (q, 2H), 3.88 (brs, 4H), 3.49 (br s, 4H), 1.82 (t, 3H), 1.44 (t, 3H) 270 557.3 559.2(CD₃OD) 9.11 (s, 1H), 9.03 (d, 2H), 8.84 (s, 1H), 8.31 (d, 1H), 8.05 (s,1H), 7.68 (d, 1H), 7.52 (dd, 1H), 4.63 (s, 2H), 4.46 (q, 2H), 3.96 (brs, 4H), 3.52 (br s, 2H), 3.44 (br s, 2H), 2.71 (t, 2H), 2.65 (t, 2H),1.43 (t, 3H) 271 573.2 575.2 (CD₃OD) 9.12 (s, 1H), 9.05 (d, 2H), 8.86(s, 1H), 8.32 (d, 1H), 8.07 (s, 1H), 7.68 (d, 1H), 7.53 (dd, 1H), 4.63(s, 2H), 4.46 (q, 2H), 4.37 (s, 2H), 4.21 (s, 2H), 3.98 (br s, 4H), 3.52(br s, 2H), 3.47 (br s, 2H), 1.44 (t, 3H) 272 500.23 502.05 1.21 (m, 9H)3.17 (s, 1H) 3.61 (m, 8H) 4.32 (q, 2H) 4.65 (s, 2H)7.56 (t, 1H) 8.10 (s,1H) 8.58 (s, 1H) 9.07 (d, 2H) 9.30 (s, 2H) 273 476 478 9.29 (s, 2H),8.66 (s, 1H), 8.02 (s, 1H), 7.95 (m, 2H), 7.59 (m, 1H), 4.76 (s, 2H),4.30 (m, 2H), 3.94-3.68 (m, 4H), 3.50-3.17 (m, 4H), 1.30 (t, 3H) 274417.1 419 9.1 (s, 2H), 9.0 (s, 2H), 8.4 (s, 1H), 7.8 (s, 1H), 7.5 (t,1H), 4.1-4.2 (q, 2H), 3.7 (s, 2H), 2.3 (s, 6H), 1.3 (t, 3H). 275 466 468— 276 445.1 447 1.33 (t, 3H) 2.06 (m, 1H) 2.26 (m, 1H) 3.88 (m, 4H) 4.33(q, 2H)5.85 (m, 1H) 6.97 (d, 1H) 7.55 (t, 1H) 7.91 (s, 1H) 8.08 (d, 1H)8.52 (m, 2H)9.05 (d, 2H) 12.44 (br s, 1H) 277 475.1 477 1.3 (t, 3H), 2.3(s, 6H), 3.35 (m, 4H), 3.9 (m, 4H), 4.3 (q, 2H), 4.6 (s, 2H), 7.7 (d,1H), 7.9 (s, 1H), 8.0 (dt, 1H), 8.3 (s, 1H), 8.35 (dd, 1H), 8.75 (d,1H), 8.8 (br s, 1H), 9.1 (d, 1H), 10.4 (br s, 1H) 278 502.1 504 1.3 (t,3H), 3.2 (s, 3H), 3.4 (br s, 4H), 3.7 (br s, 4H), 3.8 (br s, 2H), 4.3(q, 2H), 4.8 (br s, 2H), 7.55 (t, 1H), 8.0 (d, 1H), 8.5 (d, 1H), 9.0 (s,2H), 9.05 (d, 2H), 11.8 (br s, 1H), 12.6 (br s, 1H) 279 525.2 527 — 280567.2 569 (CD₃OD) 9.11 (s, 1H), 9.03 (d, 2H), 8.83 (s, 1H), 8.33 (d,1H), 8.06 (s, 1H), 7.68 (d, 1H), 7.52 (dd, 1H), 4.63 (s, 2H), 4.46 (q,2H), 3.94 (m, 4H), 3.59 (q, 2H), 3.47 (m, 4H), 1.44 (t, 3H) 281 458.15459.98 9.11 (br. s, 2H); 9.09 (s, 1H); 8.82 (d, 1H); 8.78 (br. s, 1H);8.64 (d, 1H); 8.28 (s, 1H); 8.10 (dd, 1H); 7.88 (s, 1H); 7.52 (dd, 1H);5.38 (m, 1H); 5.5-4.2 (br. s, 4H); 4.32 (q, 2H); 3.45 (m, 1H); 3.37 (m,1H); 3.12 (m, 2H); 2.05 (m, 1 282 514.2 516 10.05 (m, 1H); 9.24 (m, 1H);9.15 (d, 2H); 8.82 (d, 1H); 8.67 (d, 1H); 8.31 (s, 1H); 8.12 (m, 1H);7.90 (s, 1H); 7.53 (m, 1H); 5.52 (m, 1H); 4.32 (q, 2H); 3.78 (m, 1H);3.55-2.88 (m, 4H); 2.12 (m, 1H); 2.02 (m, 1H); 1.88 (m, 1H); 1.33 (t 283519.15 521.02 1.3 (t, 3H), 2.35 (s, 12H), 2.8 (s, 3H), 3.0-3.7 (br s,10H), 4.3 (q, 2H), 4.7 (br s, 2H), 7.6 (m, 1H), 7.9 (s, 1H), 7.95 (m,2H), 8.65 (m, 1H), 9.0 (s, 2H) 290 487.1 489 — 291 — 490 — 292 482.1 484— 293 483 484.9 — 294 460.11 461.96 1.15 (t, 3H), 2.3 (s, 9H), 3.25 (m,2H), 3.5 (m, 4H), 3.8 (m, 4H), 7.5 (br s, 1H), 7.6 (m, 1H), 7.95 (m,1H), 8.0 (s, 1H), 8.1 (m, 1H), 8.2 (m, 1H), 8.4 (d, 1H), 8.6 (s, 1H),8.7 (d, 1H), 10.3 (br s, 1H) 295 — — (CD₃OD) 9.13 (d, 1H), 9.05 (d, 2H),8.92 (d, 1H), 8.37 (m, 1H), 8.13 (d, 1H), 7.75 (dt, 1H), 7.55 (t, 1H),4.70 (s, 2H), 4.49 (q, 2H), 3.62 (m, 4H), 2.47 (m, 4H), 1.44 (t, 3H) ppm

Example 27 Gyrase ATPase Assay

The ATP hydrolysis activity of DNA gyrase was measured by coupling theproduction of ADP through pyruvate kinase/lactate dehydrogenase to theoxidation of NADH. This method has been described previously (Tamura andGellert, 1990, J. Biol. Chem., 265, 21342).

ATPase assays are carried out at 30° C. in buffered solutions containing100 mM TRIS pH 7.6, 1.5 mM MgCl₂, 150 mM KCl. The coupling systemcontains (final concentrations) 2.5 mM phosphoenol pyruvate, 200 μMnicotinamide adenine dinucleotide (NADH), 1 mM DTT, 30 ug/ml pyruvatekinase, and 10 ug/ml lactate dehydrogenase. 40 nanomolar enzyme (374 kDaGyr A2B2 subunit from Staphylococcus aureus) and a DMSO solution of theinhibitor to a final concentration of 4% are added and the reactionmixture is allowed to incubate for 10 minutes at 30° C. The reaction isthen started by the addition of ATP to a final concentration of 0.9 mMand the rate of NADH disappearance at 340 nanometers is measured overthe course of 10 minutes. The K_(i) values are determined from rateversus concentration profiles.

Compounds of the present invention were found to inhibit gyrase. Incertain embodiments, compounds of the present invention inhibit gyrasewith a K_(i) value of less than 50 nM in the above assay.

Example 28 Topo IV ATPase Assay

The conversion of ATP to ADP by Topo4 enzyme is coupled to theconversion of NADH to NAD+ and measured by the change in absorbance at340 nm. Topo4 is incubated with inhibitor (4% DMSO final) in buffer for10 minutes at 30° C. Reaction is initiated with ATP and rates aremonitored continuously for 20 minutes at 30° C. on a Molecular DevicesSpectraMAX plate reader. The inhibition constant, Ki, is determined fromplots of rate vs. [Inhibitor] fit to the Morrison Equation for tightbinding inhibitors.

S. aureus Topo4 Buffer:

100 mM Tris 7.5, 2 mM MgCl2, 200 mM K.Glutamate, 2.5 mM phosphoenolpyruvate, 0.2 mM NADH, 1 mM DTT, 4.25 μg/mL linearized DNA, 50 μg/mLBSA, 30 μg/mL pyruvate kinase, and 10 μg/mL lactate dehyrodgenase (LDH).E. coli Topo4 Buffer:

100 mM Tris 7.5, 6 mM MgCl2, 20 mM KCl, 2.5 mM phosphoenol pyruvate, 0.2mM NADH, 10 mM DTT, 5.25 μg/mL linearized DNA, 50 μg/mL BSA, 30 μg/mLpyruvate kinase, and 10 μg/mL lactate dehyrodgenase (LDH).

Compounds of the present invention were found to inhibit TopoIV. Incertain embodiments, compounds of the present invention inhibit TopoIVwith a K_(i) value of less than 50 nM in the above assay.

Example 29 Susceptibility Testing in Liquid Media

Compounds of this invention were also tested for antimicrobial activityby susceptibility testing in liquid media. Such assays were performedwithin the guidelines of the latest NCCLS document governing suchpractices: “M7-A5 Methods for dilution Antimicrobial SusceptibilityTests for Bacteria that Grow Aerobically; Approved Standard—FifthEdition (2000)”. Other publications such as “Antibiotics in LaboratoryMedicine” (Edited by V. Lorian, Publishers Williams and Wilkins, 1996)provide essential practical techniques in laboratory antibiotic testing.Essentially, several discrete bacterial colonies of Staphylococcusaureus (3 to 7) from a freshly streaked plate were transferred to anappropriate rich broth medium such as MHB, supplemented whereappropriate for the more fastidious organisms. This was grown overnightto high density followed by a 1 or 2-thousand-fold dilution to give aninoculation density of between 5×10⁵ and 5×10⁶ CFU per mL.Alternatively, the freshly picked colonies can be incubated at 37° C.for about 4 to 8 hours until the culture equals or exceeds a turbidityof a 0.5 McFarland standard (approximately 1.5×10⁸ cells per mL) anddiluted to give the same CFU per mL as above. In a more convenientmethod, the inoculum was prepared using a commercially availablemechanical device (the BBL PROMPT System) that involves touching fivecolonies directly with a wand, containing crosshatch grooves at itsbottom, followed by suspension of the bacteria in an appropriate volumeof saline. Dilution to the appropriate inoculum cell density was madefrom this cell suspension. The broth used for testing consists of MHBsupplemented with 50 mg per L of Ca²⁺ and 25 mg per L of Mg²⁺. Standarddilution panels of control antibiotics were made and stored as in theNCCLS standard M7-A5, the dilution range typically being in the 128 μgper mL to 0.015 μg per mL (by 2-fold serial dilution). The testcompounds were dissolved and diluted fresh for experimentation on thesame day; the same or similar ranges of concentration as above beingused. The test compounds and controls were dispensed into a multiwellplate and test bacteria added such that the final inoculation wasapproximately 5×10⁴ CFU per well and the final volume was 100 μL. Theplates were incubated at 35° C. overnight (16 to 20 hours) and checkedby eye for turbidity or quantitated with a multiwell plate reader. Theendpoint minimal inhibitory concentration (MIC) is the lowestconcentration of drug at which the microorganism tested (Staphylococcusaureus) does not grow. Such determinations were also compared to theappropriate tables contained in the above two publications to ensurethat the range of antibacterial activity is within the acceptable rangefor this standardized assay.

Compounds of the present invention were found to have antimicrobialactivity in the above-described S. aureus MIC assay.

While we have described a number of embodiments of the presentinvention, it is apparent that our basic constructions may be altered toprovide other embodiments which utilize the products and processes ofthis invention.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: W is selectedfrom nitrogen, CH, or CF; X is selected from CH or CF; Z is O or NH; R¹is phenyl or a 5-6 membered heteroaryl ring having 1-3 heteroatomsindependently selected from oxygen, nitrogen, or sulfur, wherein: R¹ issubstituted with 0-3 groups independently selected from -(T)_(y)-Ar, R′,oxo, C(O)R′, CO₂R′, OR′, N(R′)₂, SR′, NO₂, halogen, CN, C(O)N(R′)₂,NR′C(O)R′, SO₂R′, SO₂N(R′)₂, or NR′SO₂R′; y is 0 or 1; T is a straightor branched C₁₋₄ alkylidene chain, wherein one methylene unit of T isoptionally replaced by —O—, —NH—, or —S—; each R′ is independentlyselected from hydrogen, C₁₋₄ aliphatic, or a 5-6 membered saturated,unsaturated, or aryl ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, wherein: R′ is substituted with 0-3groups independently selected from halogen, oxo, R^(o), N(R^(o))₂,OR^(o), CO₂R^(o), NR^(o)C(O)R^(o), C(O)N(R^(o))₂, SO₂R^(o),SO₂N(R^(o))₂, or NR^(o)SO₂R^(o), wherein: each R^(o) is independentlyselected from hydrogen, C₁₋₄ aliphatic, or a 5-6 membered saturated,unsaturated, or aryl ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, and wherein: two substituents onadjacent positions of R¹ may be taken together to form a 5-7 memberedsaturated, partially unsaturated, or aryl ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; Ar is a 3-8membered saturated, unsaturated, or aryl ring, a 3-7 memberedheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein: Ar is substituted with 0-3 groups independently selected fromR′, oxo, CO₂R′, OR′, N(R′)₂, SR′, NO₂, halogen, CN, C(O)N(R′)₂,NR′C(O)R′, SO₂R′, C(O)R′, SO₂N(R′)₂, or NR′SO₂R′; R² is selected fromhydrogen or a C₁₋₃ aliphatic group; and Ring A is a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, provided that said ring has a hydrogen-bondacceptor in the position adjacent to the point of attachment to Ring B,wherein: Ring A is substituted with 0-3 groups independently selectedfrom R′, oxo, CO₂R′, OR′, N(R′)₂, SR′, NO₂, halogen, CN, C(O)N(R′)₂,NR′C(O)R′, SO₂R′, SO₂N(R′)₂, or NR′SO₂R′, and wherein: two substituentson adjacent positions of Ring A may be taken together to form a 5-7membered saturated, partially unsaturated, or aryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur. 2.The compound according to claim 1, wherein Ring A is selected from thefollowing optionally substituted rings:


3. The compound according to claim 2, wherein Ring A is an optionallysubstituted ring selected from rings a, f, l, s, w, y, or z:


4. The compound according to claim 1, wherein: R¹ is selected from anoptionally substituted phenyl or 5-6 membered heteroaryl ring having 1-2nitrogens.
 5. The compound according to claim 4, wherein R¹ is anoptionally substituted ring selected from pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,pyrimidin-6-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, orimidazol-5-yl.
 6. The compound according to claim 5, wherein R¹ issubstituted with 0-2 groups independently selected from halogen, oxo,R′, CO₂R′, OR′, N(R′)₂, SR′, C(O)N(R′)₂, NR′C(O)R′, SO₂R′, SO₂N(R′)₂, orNR′SO₂R′.
 7. The compound according to claim 6, wherein R² is selectedfrom methyl, ethyl, isopropyl, or cyclopropyl.
 8. The compound accordingto claim 1, wherein said compound is of formula II-a:

or a pharmaceutically acceptable salt thereof.
 9. The compound accordingto claim 1, wherein said compound is of formula III:

or a pharmaceutically acceptable salt thereof, wherein: the pyridonering depicted is substituted with 0-2 groups independently selected fromhalogen, oxo, R′, CO₂R′, OR′, N(R′)₂, SR′, C(O)N(R′)₂, NR′C(O)R′, SO₂R′,SO₂N(R′)₂, or NR′SO₂R′.
 10. The compound according to claim 9, whereinsaid compound is of formula III-a:

or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 10, wherein: R′ is hydrogen or C₁₋₄ aliphatic, andwherein: R′ is optionally substituted with phenyl or pyridyl.
 12. Thecompound according to claim 1, wherein said compound is of formula IV:

or a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 12, wherein Ar is an optionally substituted 5-6membered saturated ring having 1-2 heteroatoms independently selectedfrom oxygen, nitrogen, or sulfur.
 14. The compound according to claim12, wherein Ar is an optionally substituted 5-membered heteroaryl ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur.
 15. The compound according to claim 12, wherein Ar is anoptionally substituted 6-membered heteroaryl ring having 1-3 nitrogens.16. The compound according to claim 12, wherein Ar is optionallysubstituted phenyl.
 17. The compound according to claim 1, wherein saidcompound is of formula V:

or a pharmaceutically acceptable salt thereof.
 18. The compoundaccording to claim 17, wherein said compound is of formula VI:

or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to any one of claims 8, 11, 12, or 17 wherein R² is ethyl. 20.A compound selected from the group consisting of:


21. A composition comprising a compound according to claim 1, and apharmaceutically acceptable carrier, adjuvant, or vehicle.
 22. Thecomposition according to claim 21, additionally comprising an additionaltherapeutic agent selected from an antibiotic, an anti-inflammatoryagent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, acytokine antagonist, an immunosuppressant, an anti-cancer agent, ananti-viral agent, a cytokine, a growth factor, an immunomodulator, aprostaglandin, an anti-vascular hyperproliferation compound, or an agentwhich increases the susceptibility of bacterial organisms toantibiotics.
 23. A method of inhibiting gyrase activity in a biologicalsample or in a patient, comprising the step of contacting saidbiological sample with: a) a composition according to claim 21; or b) acompound according to claim
 1. 24. A method of inhibiting TopoIVactivity in a biological sample or in a patient, comprising the step ofcontacting said biological sample with: a) a composition according toclaim 21; or b) a compound according to claim
 1. 25. A method ofinhibiting gyrase and TopoIV activity in a biological sample or in apatient, comprising the step of contacting said biological sample with:a) a composition according to claim 21; or b) a compound according toclaim
 1. 26. A method of decreasing bacterial quantity in a patient,comprising the step of administering to said patient: a) a compositionaccording to claim 21; or b) a compound according to claim
 1. 27. Amethod of treating, preventing, or lessening the severity of, abacterial infection in a patient, comprising the step of administeringto said patient: a) a composition according to claim 21; or b) acompound according to claim
 1. 28. The method according to claim 27,wherein the bacterial infection to be treated is characterized by thepresence of one or more of the following: Streptococcus pneumoniae,Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium,Klebsiella pneumoniae, Enterobacter sps. Proteus sps. Pseudomonasaeruginosa, E. coli, Serratia marcesens, Staphylococcus aureus, Coag.Neg. Staph, Haemophilus influenzae, Bacillus anthracis, Mycoplasmapneumoniae, Moraxella catarralis, Chlamydia pneumoniae, Legionellapneumophila, Staphylococcus epidermidis, Mycobacterium tuberculosis, orHelicobacter pylori.
 29. The method according to claim 28, wherein thebacterial infection to be treated is selected from one or more of thefollowing: a urinary tract infection, a respiratory infection,pneumonia, prostatitis, a skin or soft tissue infection, anintra-abdominal infection, a blood stream infection, or an infection offebrile neutropenic patients.
 30. The method according to claim 29,further comprising the step of administering to said patient anadditional therapeutic agent either as part of a multiple dosage formtogether with said compound or as a separate dosage form.
 31. The methodaccording to claim 28, further comprising the step of administering tosaid patient an agent that increases the susceptibility of bacterialorganisms to antibiotics.